Hostname: page-component-78c5997874-lj6df Total loading time: 0 Render date: 2024-10-30T13:48:36.528Z Has data issue: false hasContentIssue false

Carotenoid metabolites, their tissue and blood concentrations in humans and further bioactivity via retinoid receptor-mediated signalling

Published online by Cambridge University Press:  16 November 2022

Torsten Bohn
Affiliation:
Nutrition and Health Research Group, Precision Health Department, Luxembourg Institute of Health, 1 A-B, rue Thomas Edison, L-1445, Strassen, Luxembourg
Angel R. de Lera
Affiliation:
Departmento de Química Orgánica, Facultade de Química, CINBIO and IBIV, Universidade de Vigo, 36310 Vigo, Spain
Jean-Francois Landrier
Affiliation:
Aix-Marseille University, C2VN, INRAe, INSERM, Marseille, France
Ralph Rühl*
Affiliation:
CISCAREX UG, Berlin, Germany Paprika Bioanalytics BT, Debrecen, Hungary
*
*Corresponding author. Ralph Rühl, email: ralphruehl@web.de
Rights & Permissions [Opens in a new window]

Abstract

Many epidemiological studies have emphasised the relation between carotenoid dietary intake and their circulating concentrations and beneficial health effects, such as lower risk of cardiometabolic diseases and cancer. However, there is dispute as to whether the attributed health benefits are due to native carotenoids or whether they are instead induced by their metabolites. Several categories of metabolites have been reported, most notably involving (a) modifications at the cyclohexenyl ring or the polyene chain, such as epoxides and geometric isomers, (b) excentric cleavage metabolites with alcohol-, aldehyde- or carboxylic acid-functional groups or (c) centric cleaved metabolites with additional hydroxyl, aldehyde or carboxyl functionalities, not counting their potential phase-II glucuronidated / sulphated derivatives. Of special interest are the apo-carotenoids, which originate in the intestine and other tissues from carotenoid cleavage by β-carotene oxygenases 1/2 in a symmetrical / non-symmetrical fashion. These are more water soluble and more electrophilic and, therefore, putative candidates for interactions with transcription factors such as NF-kB and Nrf2, as well as ligands for RAR–RXR nuclear receptor interactions. In this review, we discuss in vivo detected apo-carotenoids, their reported tissue concentrations, and potential associated health effects, focusing exclusively on the human situation and based on quantified / semi-quantified carotenoid metabolites proven to be present in humans.

Type
Review Article
Copyright
© The Author(s), 2022. Published by Cambridge University Press on behalf of The Nutrition Society

Introduction

Carotenoids are typically colourful, mostly C-40-based pigments that are generally obtained via plant food items. Over 1100 different carotenoids have been identified(Reference Yabuzaki1), and additional new carotenoids are being discovered, including shorter (C-30), and longer (C-50) analogues of bacterial origin(Reference Rodriguez-Concepcion, Avalos and Bonet2). Likewise, apo-carotenoids, carotenoid breakdown products formed in plants(Reference Felemban, Braguy, Zurbriggen and Al-Babili3) or after human ingestion(Reference Harrison and Quadro4), can be considered to belong to this group.

The interest in these secondary plant compounds has increased considerably in the past two to three decades, due to the relation of their intake and circulating plasma concentrations with chronic disease risk. A high carotenoid intake within a plant-food-rich diet and carotenoid concentrations in plasma have been related, among others, to a reduced risk of type-2 diabetes(Reference Sluijs, Cadier, Beulens, van der, Spijkerman and van der Schouw5), age-related macular degeneration(Reference Zhou, Zhao and Johnson6), some types of cancer such as those of the prostate(Reference Dulińska-Litewka, Hałubiec, Łazarczyk, Szafrański, Sharoni, McCubrey, Gąsiorkiewicz and Bohn7), and even total mortality(Reference Zhao, Zhang, Zheng, Li, Zhang, Tang and Xiang8). The underlying mechanisms for such associated health benefits are not quite clear and are the topic of controversial discussions, but potential mechanisms include direct antioxidant effects such as quenching of singlet oxygen and lipid peroxides(Reference Krinsky and Johnson9), interactions with transcription factors related to inflammatory pathways (e.g. NF-kB) and oxidative stress (e.g., Nrf-2)(Reference Bohn10), and also their interaction with the nuclear factors retinoid-X receptors (RXRs) and retinoic acid receptors (RARs) together with peroxisome proliferator-activated receptors (PPARs)(Reference Bonet, Canas, Ribot and Palou11Reference Mounien, Tourniaire and Landrier13).

It has also been postulated that the potential health benefits are conveyed not necessarily by the native carotenoids, following their absorption in the small intestine, but by their metabolites / cleavage products. Carotenoids as lipophilic constituents are absorbed following their micellisation into enterocytes, where they may partly undergo cleavage by carotenoid oxygenases, namely BCO1 and BCO2, resulting in the formation of symmetrical or non-symmetrical cleavage products(Reference Amengual, Widjaja-Adhi, Rodriguez-Santiago, Hessel, Golczak, Palczewski and von Lintig14).

While some of the symmetrical cleavage products have vitamin A activity (following e.g. cleavage of β-carotene or β-cryptoxanthin) by BCO1, the biological role of the other cleavage products remains uncertain. These cleavage products or apo-carotenoids have been proposed to be bioactive. For instance, in in vitro studies, lycopene derivatives were shown to have higher affinity to Nrf-2 and NF-kB, due to their higher electrophilicity, and perhaps better aqueous solubility(Reference Linnewiel, Ernst, Caris-Veyrat, Ben-Dor, Kampf, Salman, Danilenko, Levy and Sharoni15Reference Bruzzone, Ameri and Briatore19). Lycopene has been shown to act in part similarly to vitamin A metabolites in normalising a vitamin-A-deficient diet in rats / mice(Reference Aydemir, Kasiri, Bartok, Birta, Frohlich, Bohm, Mihaly and Rühl20). It cannot also be excluded that bacteria in the colon produce more hydrophilic metabolites of carotenoids that are bioavailable and bioactive(Reference Dingeo, Brito, Samouda, La Frano and Bohn21).

Therefore, there has been increased interest in carotenoid metabolites and their potential connection to health benefits. A limitation of their detection in human specimens is the lack of commercial standards, in addition to their lower concentration and the lower sensitivity of UV- detection, the most common technique employed in their quantification, due to the shortened delocalised electron system in the molecule.

In this review, we strive to present the current state of knowledge of metabolites and breakdown product of carotenoids in humans, their known concentration ranges, and potential health benefits involved, as well as pointing out gaps and potential ways forward in this research domain. In this review, we focused exclusively on the human situation, owing to the proven presence of the described carotenoids and carotenoid metabolites in humans.

Carotenoid metabolites in plasma and tissues

Rationale for interest in metabolites and overview of metabolites

Carotenoids, with major human food relevance (Fig. 1 and Table 1), were investigated mainly for their metabolism in the human body, and it is uncertain whether the native compounds alone or rather their metabolites are responsible for the attributed health effects. Mainly nuclear hormone receptor-mediated effects were the focus of these studies(Reference Evans and Mangelsdorf22,Reference Mangelsdorf, Thummel and Beato23) . These ligand-activated receptors include RARs and RXRs, which may become activated, resulting in altered gene expression of a large set of genes involved in inflammation, differentiation, proliferation and lipid metabolism / homoeostasis(Reference Balmer and Blomhoff24Reference Karkeni, Bonnet, Astier, Couturier, Dalifard, Tourniaire and Landrier27).

Fig. 1. Metabolic pathway starting from all-trans-β-carotene and all-trans-lycopene via (a) geometric isomerisation, (b) eccentric cleavage metabolism and (c) centric-cleavage mechanisms. Starting from food, towards transport and intermediate derivatives, nuclear hormone receptor activating ligands including further regulation of transcription and thereby major mediation of biological signalling of carotenoids and further deactivation / excretion metabolites. Arrows in the figure indicate potential and simplified metabolic pathways. Derivatives that were not conclusively identified to be present endogenously in humans were marked with a star (*) and represent derivatives which that were suggested as metabolites and identified in in vitro or in vivo experimental approaches. Additional derivatives, which were predicted based on analytical studies, were indicated by two starts (**). Abbreviations: AT: all-trans-, RAR: retinoic acid receptor, RXR: retinoid-X receptor.

Table 1. Concentrations of carotenoids in various tissues, all data in nM (nmol/kg or L), adapted from ref.(Reference Böhm, Borel and Corte-Real97)

All values represent mean ± SD; ‘blank’ represents non-determined carotenoids or no data available.

$ , infants, prefrontal cortex, frontal cortex, hippocampus, auditory cortex and occipital cortex.

£ , values given in literature as ‘carotenes’.

& , dermis and epidermis of back, forehead, inner forearm and hand.

* , including upper and lower level of this range.

** , indicates a value as a potential sum of BCAR and ACAR.

ACAR, α-carotene; BCAR, β-carotene; BCRY, β-cryptoxanthin; LYC, lycopene; PHYE, phytoene; PHYF, phytofluene; CBC: cis-β-carotene; CLC: cis-lycopene; ATLYC: all-trans-lycopene; ATBC: all-trans β-carotene.

The activation of RARs and / or RXRs was shown to be related to physiologically and nutritionally relevant levels of endogenous carotenoid metabolites(Reference Mangelsdorf, Ong, Dyck and Evans28Reference Petkovich, Brand, Krust and Chambon31). Thus, native carotenoids may not interact on their own with gene-regulatory pathways, but rather via their metabolites, the apo-carotenoids, here conclusively the apo-15-carotenoids / retinoids and potentially others, such as apo-13/14-carotenoids that might interact with the binding grooves of RARs and RXRs(Reference Eroglu, Hruszkewycz and dela Sena32Reference Schierle and Merk34). Here, a focus for activating compounds is put on apo-carotenoids with an acid functionality, while apo-carotenoids with aldehyde or alcohol functionalities might result in low affinity activators / antagonistic compounds(Reference Schierle and Merk34). Consequently, knowing more on their identity, concentration, metabolic pathways and homeostatic control and further RAR-RXR-mediated signalling appears critical for estimating potential health benefits of carotenoids(Reference Schmidt, Brouwer and Nau35Reference Allenby, Janocha, Kazmer, Speck, Grippo and Levin39) (Tables 1 and 2).

Table 2. Levels of major carotenoid metabolites / retinoids in blood plasma / serum and tissues including molecular weight in Dalton (Da) and molecular formula of each retinoid

* , likely just an isomerisation product of ATRA during sample preparation.

** , present in different concentrations in different zones of the human skin.

*** , healthy adults.

**** , all-trans-retinol levels in mouse are just used as reference for comparison with 9-cis- and 13-cis-retinol levels, which were just determined in mouse serum and not in humans.

***** , derivatives which were predicted by analytical studies.

# , 9,13-dicis- and 13-cis-retinoic acid usually co-elute during HPLC separation and are not identified separately in many described studies.

(1): 4-oxo-retinoic acid was described as an in vitro metabolite of canthaxanthin(Reference Stahl, Hanusch and Sies182).

BCAR, β-carotene; LYC, lycopene; CA, canthaxanthin; WAT, white adipose tissue; end., endogenous; supp., supplementation; ecnd, exact concentration was not determined.

Individual carotenoids, listed in Table 1 along with their endogenous levels in serum / plasma as well as selected organs, may be cleaved by either BCO1 (centric cleavage) or BCO2 (excentric cleavage) to produce a variety of apo-carotenoids / retinoids (Fig. 1 and Tables 1 and 2)(Reference dela Sena, Narayanasamy, Riedl, Curley, Schwartz and Harrison40,Reference dela Sena, Sun, Narayanasamy, Riedl, Yuan, Curley, Schwartz and Harrison41) .

In general, there are three different types of carotenoid metabolites that occur in human plasma / serum and tissues and have been detected especially after carotenoid supplementation: (a) non-cleaved carotenoids with modifications at the cyclohexenyl ring or the polyene chain, such as epoxycarotenoids, geometric isomers and metabolites resulting from further rearrangement pathways; (b) excentrically cleaved metabolites with also alcohol, aldehyde or carboxylic acid functionalities; and (c) centrically cleaved metabolites with additional alcohol, aldehyde or carboxylic acid functionalities (Fig. 1 and Tables 1 and 2). Of note, glucuronidated products are also formed, following phase II conjugation, prior to their excretion via the kidney, as reported, for example, for retinoic acids(Reference Barua and Olson42Reference Radominska, Little, Lehman, Samokyszyn, Rios, King, Green and Tephly44).

The origin of selected apo-15-carotenoids / retinoid derivatives, such as retinyl esters, retinol, retinal and retinoic acids, might occur from various metabolic pathways including (a) central cleavage of individual carotenoids such as β-carotenes or β-cryptoxanthins (Fig. 1) by BCO1 cleavage(Reference Amengual, Lobo, Golczak, Li, Klimova, Hoppel, Wyss, Palczewski and von Lintig45Reference Kiefer, Hessel, Lampert, Vogt, Lederer, Breithaupt and von Lintig47); (b) by interaction of these previously mentioned carotenoids with environmental or endogenous oxidants and following cleavage(Reference Bohn10,Reference Caris-Veyrat, Schmid, Carail and Böhm48,Reference Bohn, Desmarchelier, El, Keijer, van Schothorst, Rühl and Borel49) ; or (c) by BCO1 cleavage of individual apo-carotenoids, which might originate from food directly or from mitochondrially based BCO2 cleavage in the human organism(Reference Amengual, Widjaja-Adhi, Rodriguez-Santiago, Hessel, Golczak, Palczewski and von Lintig14,Reference Amengual, Lobo, Golczak, Li, Klimova, Hoppel, Wyss, Palczewski and von Lintig45,Reference Kiefer, Hessel, Lampert, Vogt, Lederer, Breithaupt and von Lintig47) .

Alternatively, these apo-15-carotenoids / retinoids might originate from food-derived apo-15-carotenoids present at high concentration in animal-derived food matrices, such as retinol and retinyl esters, or from bioactive retinoids, such as retinoic acids and retinal, which are present in low amounts in the food matrix. Unfortunately, it is not possible to quantitatively describe which derivative originated from which individual pathway, or even at which percentile amount, due to the large variety of individually consumed food sources and individual enzymatic pathways present in humans(Reference Bohn, Desmarchelier, El, Keijer, van Schothorst, Rühl and Borel49Reference Bohn, Bonet and Borel51).

Interestingly, some studies have reported that blood and tissue concentrations of active vitamin A retinoids differ significantly between disease and health state (reviewed in ref.(52)). These results raise the question as to whether the differences in such levels are caused by the disease or whether low intake of carotenoids has led to the development of these conditions. It appears that, at least in inflammation-related diseases, vitamin A active compounds are often less abundant in plasma, likely as a consequence and not as a cause of the disease(Reference Rubin, Ross, Stephensen, Bohn and Tanumihardjo52), as a potential feedback to counteract inflammation mediated by bioactive vitamin A derivatives induced by pro-inflammatory RAR- and RXR-mediated signalling(Reference Al Senaidy53,Reference Nogueira, Borges, Lameu, Franca, Rosa and Ramalho54) .

In many countries, shortage of food and especially vitamin A deficiencies are still common(Reference Akhtar, Ahmed, Randhawa, Atukorala, Arlappa, Ismail and Ali55), and supplementation with provitamin A carotenoids / vitamin A appears to be a prudent strategy. However, in our Western society, vitamin A intakes are very often quite high, while carotenoid intake is generally lower(56,Reference Biehler, Alkerwi, Hoffmann, Krause, Guillaume, Lair and Bohn57) . This has partly been associated with pathophysiological situations(Reference Aage, Kiraly, Da Costa, Byberg, Bjerregaard-Andersen, Fisker, Aaby and Benn58Reference Crandall63). Whether increased all-trans-retinoic acid (ATRA) concentrations in plasma or tissue following carotenoid supplementation are purely beneficial has thus been the subject of controversial discussion(Reference Mihaly, Gericke, Lucas, de Lera, Alvarez, Torocsik and Rühl64Reference Gruber, Taner, Mihaly, Matricardi, Wahn and Rühl67). The lipid hormone ATRA has been described to be associated with cell differentiation, proliferation and apoptosis with beneficial relevance mainly for cancer prevention(Reference Wei, Kozono and Kats68,Reference Connolly, Nguyen and Sukumar69) , and various diseases related to reduced inflammatory competence(Reference Tan, Sande, Pufnock, Blattman and Greenberg70,Reference Saiag, Pavlovic, Clerici, Feauveau, Nicolas, Emile and Chastang71) . Unfortunately, ATRA has also been associated with toxic effects, especially embryonic toxicity(Reference Tzimas and Nau72,Reference David, Hodak and Lowe73) .

Recently, ATRA has been discussed more controversially in the context of diabetes, obesity, allergies and osteoporosis(Reference Govind Babu, Lokesh, Suresh Babu and Bhat74Reference Trasino and Gudas76). Especially the adverse effects of retinoids regarding inflammatory processes, related to many diseases in Western societies, and alteration of local and systemic lipid metabolism and homoeostasis are regarded as critical(Reference David, Hodak and Lowe73,Reference Rühl, Garcia, Schweigert and Worm77,Reference Wansley, Yin and Prussin78) . Therefore, it must be carefully evaluated whether retinoid / carotenoid supplementation in such countries is generally beneficial.

General properties of metabolites originating from β-carotene and β-cryptoxanthin

When focusing on β-carotene, we may obtain a large variety of known and yet unknown, although partly postulated, metabolites (Fig. 1). In this chapter, β-carotene isomers such as α- or γ-isoforms of carotene, geometric isomers of these carotenes, were included, as well as the provitamin A carotenoid β-cryptoxanthin as a relevant precursor for the carotenoid metabolites addressed later in this subchapter (Fig. 1 and Table 1).

Firstly, several chain-modified carotenoid metabolites have been identified, including in mammals and human serum, with epoxy-, oxo- and hydroxyl-containing functional groups located at the cyclohexenyl ring or at the polyene chain, as well as additional isomers(Reference Khachik, Spangler, Smith, Canfield, Steck and Pfander79,Reference Britton, Liaaen-Jensen and Pfander80) . Whether these metabolites originate from plant-based metabolism or from mammalian endogenous metabolism is not always obvious. Concentrations of these potential metabolites, which are usually lower than those of their parent direct / indirect nutritional precursor all-trans-β-carotene, are rarely reported. Precise quantification presents a challenge, owing to the lack of commercially available standards and also lower UV–Vis sensitivity.

Several similar compounds may also be generated during digestion or food processing(Reference Britton, Liaaen-Jensen and Pfander80). For example, upon gastrointestinal exposure to oxidising agents, such as iron, a large variety of degradation products in the intestine have been reported, including several β-apo-carotenals(Reference Kopec, Caris-Veyrat, Nowicki, Gleize, Desmarchelier and Borel81), epoxides and diketones(Reference Sy, Dangles, Borel and Caris-Veyrat82). On the other hand, many reports have stated that carotenoids from plant matrices remain relatively stable upon in vitro digestion, as demonstrated for β-carotene(Reference Ferruzzi, Lumpkin, Schwartz and Failla83), lutein(Reference Granado-Lorencio, Olmedilla-Alonso, Herrero-Barbudo, Perez-Sacristan, Blanco-Navarro and Blazquez-Garcia84) and lycopene(Reference Richelle, Sanchez, Tavazzi, Lambelet, Bortlik and Williamson85). Whether such degradation products can be absorbed, and whether they are then further metabolised in vivo, remains unknown(Reference Kopec, Caris-Veyrat, Nowicki, Gleize, Desmarchelier and Borel81).

Various apo-carotenoids originating from excentric cleavage of carotenoids were identified in mammals and partly in the human organism after carotenoid supplementation(Reference Eroglu and Harrison86,Reference Harrison, dela Sena, Eroglu and Fleshman87) . Both BCO1 and BCO2 appear able to cleave β-carotene. While BCO1 appears to favour full-length provitamin A carotenoids resulting in centric cleavage, BCO2 appears to cleave both provitamin A carotenoids and xanthophylls excentrically(Reference dela Sena, Narayanasamy, Riedl, Curley, Schwartz and Harrison40,Reference dela Sena, Sun, Narayanasamy, Riedl, Yuan, Curley, Schwartz and Harrison41,Reference Bandara, Thomas, Ramkumar, Khadka, Kiser, Golczak and von Lintig88) and is induced in BCO1−/− mice adipose tissue, leading to β-apo-10’-carotenol accumulation(Reference Amengual, Gouranton and van Helden89). It is possible that some of these metabolites are themselves substrates for BCO1/2, as indicated for β-apo-8′-carotenal, β-apo-10′-carotenal, β-apo-12′-carotenal and β-apo-14′-carotenal in chicken and rats(Reference Eroglu and Harrison86,Reference Kim and Oh90,Reference Harrison91) . Unfortunately, as already outlined, a clear ordination as to which individual carotenoid metabolite is created by which specific individual metabolic pathway with specific substrate / product derivatives is not possible due to the large diversity of food sources and individual human enzymatic pathways(Reference Bohn, Desmarchelier, El, Keijer, van Schothorst, Rühl and Borel49,Reference Böhm, Lietz and Olmedilla-Alonso92) . This large variety of food sources with individual carotenoid-metabolite precursors and endogenous enzymatic pathways is an important feature of the mammalian organism(Reference Bohn, Desmarchelier, El, Keijer, van Schothorst, Rühl and Borel49,Reference Böhm, Lietz and Olmedilla-Alonso92) . It entails the use of various regionally and timely restricted available food sources to create and degrade ligands for nuclear hormone receptors to enable normal healthy biological functions. This also includes auto-regulative metabolic and uptake pathways to regulate ligand creation and degradation, as exemplified and described in detail in a review relevant for β-carotene(Reference Bohn, Desmarchelier, El, Keijer, van Schothorst, Rühl and Borel49), outlined in Fig. 1.

Different apo-carotenals and apo-carotenoic acids of various chain lengths were found after β-carotene supplementation(Reference Eroglu and Harrison86,Reference Harrison, dela Sena, Eroglu and Fleshman87) . These were then synthesised ex vivo and further studied in molecular biological experiments, and partly identified after direct supplementation of β-carotene and food items rich in β-carotene. These described apo-carotenoids are of different chain lengths, ranging from apo-8′-, apo-10′-, apo-12′- and apo-14′-carotenals, and can further be oxidised to apo-carotenoic acids (Fig. 1). Contrarily, endogenously produced levels have rarely been described, only for selected derivatives(Reference Ho, de Moura, Kim and Clifford93). Following the ingestion of tomato juice high in β-carotene (360 ml, 30 mg β-carotene, 35 μg apo-carotenoids per day), only apo-10′- and 12′-carotenal were reported to be detected in plasma of some individuals under the set quantification limit, though unfortunately without any added visualised analytical confirmation(Reference Cooperstone, Riedl, Cichon, Francis, Curley, Schwartz, Novotny and Harrison94). It could not be distinguished whether these were absorbed or formed de novo in vivo (Reference Kopec, Caris-Veyrat, Nowicki, Gleize, Desmarchelier and Borel81,Reference Cooperstone, Riedl, Cichon, Francis, Curley, Schwartz, Novotny and Harrison94) . In a study by Kopec et al. (Reference Kopec, Caris-Veyrat, Nowicki, Gleize, Desmarchelier and Borel81), (13C-10)-β-carotene was administered to healthy subjects. Though non-symmetrical β-apo-carotenals were found in the gut, none was observed in the plasma TRL fraction, suggesting a low bioavailability.

Following excentric cleavage, shorter products such as β-ionone, β-cyclocitral and related derivatives have been described in vitro as well as in animals(Reference dela Sena, Sun, Narayanasamy, Riedl, Yuan, Curley, Schwartz and Harrison41,Reference Sommerburg, Langhans and Arnhold95) . Carotenoid metabolites, originating from two-side carotenoid cleavage, were also described as carotenedials in vitro, including rosafluene and crocetindial(Reference Amengual, Lobo, Golczak, Li, Klimova, Hoppel, Wyss, Palczewski and von Lintig45), but these have not yet been identified in vivo and thereby were also not further investigated regarding physiologically relevant nuclear hormone-mediated signalling.

Finally, and possibly most important for the biological activity of carotenoids, centric-cleavage metabolites have been described. These metabolites of β-carotene, α-carotene and β-cryptoxanthin are the apo-15-carotenoic acids, termed retinoic acids(Reference von Lintig and Wyss96). Retinoic acids are well-known endogenous derivatives, functioning as lipid hormone receptor ligands, responsible for activating two major families of nuclear hormone receptors, that is, the RARs and RXRs. These receptors can, following ligand activation, modify transcription of receptor-specific genes(Reference Evans and Mangelsdorf22,Reference Mangelsdorf, Thummel and Beato23) . The major products are retinoic acids, mainly in the form of ATRA, the endogenous ligand of the RARs (RARα, β, γ), as reviewed previously(Reference Petkovich, Brand, Krust and Chambon31). Endogenous levels of ATRA in serum / plasma were in the range of 0·8–2·8 ng/ml (2·7–9·3 nM) and up to 6 ng/g (20 nM) in the pancreas and 16 ng/g (53 nM) in the liver (Table 2). Thus, these concentrations are at least one to two magnitudes lower than those of β-carotene in the bloodstream, with concentrations of approximately 0·1–2 µM (Table 1 (Reference Böhm, Borel and Corte-Real97)). While these centric cleavage products are the main activators of RARs and RXRs(Reference Allenby, Bocquel and Saunders38,Reference Allenby, Janocha, Kazmer, Speck, Grippo and Levin39) , the excentric apo-carotenoid apo-13-carotenone is present at lower endogenous levels of 0·8–1·3 ng/ml (3–5 nM) and has been demonstrated to act as ‘antagonist’ or low-affinity partial agonist or competitive antagonist, but the physiological and nutritional relevance is not yet known(Reference Eroglu, Hruszkewycz and dela Sena32,Reference Harrison, dela Sena, Eroglu and Fleshman87) . The physiological and nutritional relevance of the ‘antagonism’ / partial agonist activity was never convincingly determined for humans, though in in vitro experiments, with weak and questionable prediction potential for humans, but is deemed plausible when considering endogenous concentrations in human serum (3–5 nM, Table 2 and Fig. 1).

In addition to ATRA, other geometric isomers were identified endogenously, such as 13-cis-, 9,13-dicis- and 9-cis-retinoic acid(Reference Horst, Reinhardt, Goff, Nonnecke, Gambhir, Fiorella and Napoli98Reference Sass and Nau100), with low concentrations (Table 2). A large focus was placed on 9-cis-retinoic acid (9CRA), which was postulated as ‘an’ or even ‘the’ endogenous ligand of RXRs (RXRα, β, γ)(Reference Levin, Sturzenbecker and Kazmer29,Reference Heyman, Mangelsdorf, Dyck, Stein, Eichele, Evans and Thaller30) . However, this is seen as controversial by the authors / additional experts in the field of retinoid lipidomics(Reference de Lera, Krezel and Rühl36,Reference Wolf101,Reference Rühl, Krzyzosiak and Niewiadomska-Cimicka102) focusing on ultrasensitive retinoid-lipidomics analysis, as its endogenous presence and function as a physiologically relevant lipid hormone could not be confirmed. Alternative endogenous geometric isomers of retinoic acid, including 13-cis-, 9,13-dicis- and 11-cis-retinoic acid were not described to be of relevant major biological activity mediated via the activation of RARs–RXRs(Reference Levin, Sturzenbecker and Kazmer29). For retinal, the endogenous cycle between all-trans-retinal and 11-cis-retinal in the visual cycle in the eye is well established(Reference Palczewski103,Reference von Lintig, Moon and Babino104) , but it is of no systemic relevance for the whole human organism.

For ATRA, increased serum levels of 1·2 to 2·0 ng/ml (4·0 to >6·7 nM) were found following supplementation of β-carotene-rich foods(Reference Rühl, Bub and Watzl37). Whether these increased serum levels reflect also tissue levels and increased RAR-mediated signalling was and could not be identified. The physiological and nutritional relevance in humans could also not be evaluated. This intervention with food items rich in β-carotene resulted in low and non-significant alterations of interleukin (IL) secretion and immune response as indicators of RAR-mediated signalling(Reference Watzl, Bub, Brandstetter and Rechkemmer105,Reference Watzl, Bub, Briviba and Rechkemmer106) . Whether such β-carotene interventions are beneficial for humans is questionable. Interestingly, the strongest effects were identified in the carotenoid wash-out phase prior to intervention, resulting in reduced IL-2, natural killer (NK) cell cytotoxicity and lymphocyte proliferation, a potential consequence of β-carotene (or general carotenoid) or even vitamin A deficiency and possibly reduced RAR–RXR-mediated signalling(Reference Watzl, Bub, Briviba and Rechkemmer106). These reductions were rapidly recovered after β-carotene or lycopene supplementations, likely as a consequence of recovered RAR–RXR-mediated signalling(Reference Watzl, Bub, Briviba and Rechkemmer106). In animal studies, β-carotene supplementation resulted in the recovery of vitamin A deficiency indicated by visualised RARE-mediated signalling. In addition, serum, but not liver, ATRA concentrations were improved, while retinol levels recovered and even increased(Reference Aydemir, Kasiri, Bartok, Birta, Frohlich, Bohm, Mihaly and Rühl20). It can be assumed that β-carotene supplementation can reinstate basal retinol and ATRA concentrations and RAR-mediated signalling. However, no further increase in ATRA concentrations in organs and enhanced RAR-mediated signalling could be observed as a result of increased storage and transport of retinol due to a highly regulated homoeostasis of retinoid / vitamin A / RAR-mediated signalling pathways.

Nutritionally relevant β-carotene intake mainly contributes to the anti-infective properties of vitamin A, which is commonly identified as its major activity besides ocular functions(Reference Rühl12,Reference Underwood107) . It is suggested that provitamin A carotenoids are relevant for maintaining vitamin A activity, while being of no further physiologically or nutritionally proven relevance.

In contrast, long-term high-dose supplementation of pure synthetic all-trans-β-carotene, studied in tobacco-smoke-exposed ferrets, may alter RAR–RXR-mediated signalling by a negative feedback regulation(Reference Lee, Leung and Tang108), thereby strongly reducing RARβ- and ATRA levels in the lung, as the target organ(Reference Wang, Liu, Bronson, Smith, Krinsky and Russell109,Reference Lotan110) .

In addition, it is questionable whether higher-than-basal RAR-mediated signalling is more beneficial or whether it can be considered as detrimental, while increased RXR-mediated signalling may be considered mainly beneficial(Reference Desvergne25). On the basis of these limited studies, we conclude that β-carotene can prevent general vitamin A deficiency(Reference Rühl, Bub and Watzl37,Reference Watzl, Bub, Briviba and Rechkemmer106) , reaching a plateau, while higher and pure β-carotene supplementation seems unrelated to improved health status(Reference Bohn, Desmarchelier, El, Keijer, van Schothorst, Rühl and Borel49). It seems unlikely that moderate or even high dietary consumption of natural food items rich in β-carotene and additional bioactive derivatives including other carotenoids has non-beneficial effects.

Recently, dihydro-metabolites of apo-15-carotenoids were described in mice, likely originating from 13,14-dihydroretinol(Reference Moise, Kuksa, Imanishi and Palczewski111) (Fig. 1 and Table 2). In a larger cohort study, 13,14-dihydroretinol and the novel identified endogenous all-trans-13,14-dihydroretinoic acid(Reference Moise, Alvarez and Dominguez112,Reference Bazhin, Bleul, de Lera, Werner and Rühl113) and 9-cis-13,14-dihydroretinoic acid(Reference Krezel, Rühl and de Lera33,Reference de Lera, Krezel and Rühl36,Reference Rühl, Krzyzosiak and Niewiadomska-Cimicka102) were analysed in human serum(Reference Lucas, Szklenar, Mihály, Szegedi, Töröcsik and Rühl114) as well as adipose tissue (Rühl et al. unpublished). All-trans-13,14-dihydroretinoic acid was described as a medium-affinity endogenous RAR ligand(Reference Allenby, Bocquel and Saunders38,Reference Sani, Venepally and Levin115) , and recently, 9-cis-13,14-dihydroretinoic acid (9CDHRA) became a focus of attention, as it appears to be ‘an’ or even ‘the’ physiologically and nutritionally relevant RXR ligand in mammals, serving as a novel endogenous lipid hormone(Reference Krezel, Rühl and de Lera33,Reference de Lera, Krezel and Rühl36,Reference Rühl, Krzyzosiak and Niewiadomska-Cimicka102) . Further nutritionally relevant precursors of 9CDHRA, such as 9-cis-13,14-dihydroretinol, 9-cis-dihydrocarotenoids and even the well-known 9-cis-β-carotene were recently postulated(Reference Rühl, Krezel and de Lera116) and confirmed(Reference Krężel, Rivas, Szklenar, Ciancia, Alvarez, de Lera and Rühl117) as even being a new independent vitamin A signalling pathway, termed vitamin A5 (Fig. 1)(Reference Bohn, Hellmann-Regen, de Lera, Böhm and Rühl118).

Metabolites of lycopene

In addition to β-carotene, lycopene is one of the major carotenoids present in the diet, resulting in high tissue and blood concentrations (Fig. 1 and Tables 1 and 2). However, the metabolism of lycopene has been studied to a much lesser extent compared with that of β-carotene and especially when focusing on the human situation.

Oxidative metabolism of lycopene and of additional acyclic carotenoids such as phytoene and phytofluene (Table 1) has been described(Reference Khachik, Carvalho, Bernstein, Muir, Zhao and Katz119), while such metabolism was neither conclusively observed nor the focus in studies employing lutein and other carotenoids with hydroxyl- / oxo-functional groups, such as zeaxanthin, canthaxanthin, β-cryptoxanthin and astaxanthin, which would have broader relevance for the human situation. Selected xanthophylls were described to interact and block apo-carotenoid-mediated signalling(Reference van den Berg120,Reference van den Berg and van Vliet121) , while no mechanism involving xanthophyll-metabolites was mentioned and outlined. Both excentric and centric metabolism was described for lycopene(Reference dela Sena, Narayanasamy, Riedl, Curley, Schwartz and Harrison40,Reference dela Sena, Sun, Narayanasamy, Riedl, Yuan, Curley, Schwartz and Harrison41) . With the exception of lycopenoids, there was no further focus on the identification of potential endogenous derivatives or molecular biological examination to investigate their biological activities(Reference Caris-Veyrat, Garcia, Reynaud, Lucas, Aydemir and Rühl122Reference Aydemir, Kasiri, Birta, Beke, Garcia, Bartok and Rühl124). Various lycopenals were identified and predicted in the food matrix and in the human organism after a tomato product intervention. Human serum levels were reported to be low (Fig. 1 and Table 2 (Reference Kopec, Riedl, Harrison, Curley, Hruszkewycz, Clinton and Schwartz125)).

While many studies display a complex pattern of lycopene metabolism via various pathways(Reference dela Sena, Narayanasamy, Riedl, Curley, Schwartz and Harrison40,Reference Kopec, Riedl, Harrison, Curley, Hruszkewycz, Clinton and Schwartz125Reference Wang129) , and potential lycopene metabolites were found after supplementing high amounts of lycopene in experimental animal models(Reference Aydemir, Kasiri, Birta, Beke, Garcia, Bartok and Rühl124,Reference Gouranton, Aydemir and Reynaud130Reference Gajic, Zaripheh, Sun and Erdman132) , a direct association of human relevance was only recently indirectly concluded(Reference Moran, Thomas-Ahner and Fleming133). Indirect evidence of lycopene activity and a further lycopene metabolite for RAR activation was revealed, using a RARE-luciferase-expressing mouse model(Reference Aydemir, Kasiri, Bartok, Birta, Frohlich, Bohm, Mihaly and Rühl20,Reference Aydemir, Carlsen, Blomhoff and Rühl134) . Based on RARE-mediated signalling, a partial vitamin A activity following lycopene intervention was found(Reference Aydemir, Kasiri, Bartok, Birta, Frohlich, Bohm, Mihaly and Rühl20). An identification of the involved functional metabolites was only partly achieved, and apo-15-lycopenoic acids were claimed to be present endogenously, especially after lycopene supplementation(Reference Aydemir, Kasiri, Birta, Beke, Garcia, Bartok and Rühl124,Reference Ben-Dor, Nahum and Danilenko135) .

Other lycopenoic acids might also be bioactive, as it was shown previously in a mouse study that the potential lycopene metabolite apo-10′-lycopenoic acid(Reference Hu, Liu, Ernst, Krinsky, Russell and Wang131) reduced hepatic fat accumulation(Reference Ip, Liu, Lichtenstein, von Lintig and Wang136). The physiological and nutritional relevance of apo-10′-lycopenoic acid was only shown in ferrets(Reference Hu, Liu, Ernst, Krinsky, Russell and Wang131), but could not be confirmed in vivo in mice and ex vivo for humans(Reference Gouranton, Aydemir and Reynaud130). Alternatively, due to extensive metabolism, a dihydro-apo-10′-lycopenoic acid analogue was identified and on the basis of UV and mass spectrometry characteristics predicted to be 7,8-dihydro-apo-10′-lycopenoic acid. How lycopene is metabolised to dihydro-apo-10′-lycopenoic acid and whether apo-10′-lycopenoic acid is a potential intermediate are yet unanswered questions. These dihydro-apo-10-lycopenoids are likely to be direct precursors of dihydro-apo-15-lycopenoids, which might be highly potent RAR and / or RXR ligands(Reference Aydemir, Kasiri, Birta, Beke, Garcia, Bartok and Rühl124).

Summary for carotenoid metabolites

Thus, for many metabolites it remains inconclusive whether they derive from human metabolism or are ingested via animal origin as pre-formed carotenoid metabolites in the forms of retinol and mainly retinyl esters(Reference Rühl12,Reference Rühl137) . In addition, the biological function and the concentration-dependent activity of various carotenoid metabolites besides ATRA has generally not been studied, mostly due to the lack of available standard compounds and established sensitive and selective analytical methods. Furthermore, the direct link between carotenoid intake and RAR–RXR-mediated transcriptional signalling as a multi-step procedure has not yet been proven. However, each step of this cascade has been clearly demonstrated with experimental data: (a) higher carotenoid supplementation resulting in higher carotenoid levels in supplemented individuals(Reference Watzl, Bub, Brandstetter and Rechkemmer105,Reference Muller, Bub, Watzl and Rechkemmer138) , (b) higher β-carotene levels correlating and resulting in increased ATRA concentrations(Reference Rühl, Bub and Watzl37,Reference Bohn, Desmarchelier, El, Keijer, van Schothorst, Rühl and Borel49) , (c) higher ATRA levels causing increased RAR-mediated signalling(Reference Aydemir, Carlsen, Blomhoff and Rühl134); and (d) higher RAR-mediated signalling resulting in increased individual-specific immune responses(Reference Rubin, Ross, Stephensen, Bohn and Tanumihardjo52,Reference Rühl, Garcia, Schweigert and Worm77,Reference Rühl, Hanel, Garcia, Dahten, Herz, Schweigert and Worm139,Reference Zunino, Storms and Stephensen140) and altered lipid metabolism(Reference Landrier, Kasiri and Karkeni141,Reference Rühl and Landrier142) , with partially beneficial or detrimental effects.

Recently, a novel class of bioactive carotenoid metabolites, namely strigolactones, was described to be enzymatically synthesised in certain plants, such as carlactones(Reference Al-Babili and Bouwmeester143Reference Alder, Jamil and Marzorati145) and identified as plant-relevant hormones during germination(Reference Al-Babili and Bouwmeester143) and branching inhibition(Reference Gomez-Roldan, Fermas and Brewer146). Whether these derivatives are of direct or indirect relevance for the human organism remains speculative.

In summary, human supplementation studies with food items rich in β-carotene / lycopene or supplemented β-carotene / lycopene, focusing on multi-targeted analyses, and identifying β-carotene / lycopene and retinoid concentrations and further RARE-mediated signalling, have not yet been performed and should be addressed. Due to the access of multi-omic techniques, serum markers or novel transcriptional markers of diseases(Reference Casamassimi, Federico, Rienzo, Esposito and Ciccodicola147,Reference Pedrotty, Morley and Cappola148) , possibly also co-associated with vitamin A / carotenoid deficiency or reduced RAR–RXR-mediated dysfunction(Reference Desvergne25,Reference Altucci, Leibowitz, Ogilvie, de Lera and Gronemeyer149) , should be compared with carotenoid intake and serum / plasma carotenoid / retinoid concentrations to obtain valuable correlations.

Discussion and perspectives

Several carotenoids are implicated in health-related outcomes, from AMD (lutein and zeaxanthin) to possible effects regarding cardio-metabolic diseases (predominantly, β-carotene) and diabesity / cancer (predominantly, lycopene). The dietary intake of carotenoids has also changed over time. While lycopene intake was uncommon in the pre-industrialised human diet, especially considering the primarily European-focused world view, it strongly increased in Western society, due to a high consumption of tomatoes and tomato products(Reference Jenab, Ferrari and Mazuir150).

Additionally, it became obvious that light irradiation(Reference Xu and Harvey151) and more practically relevant thermal food processing(Reference Schieber and Carle152), as also reviewed by Khoo et al.(Reference Khoo, Prasad, Kong, Jiang and Ismail153), including cooking >100°C, appears to constitute important mechanisms for carotenoid isomerisation, yielding different precursor carotenoids for different functional apo-carotenoids, as well as non-endogenous human-generated apo-carotenoids, serving as easy accessible substrates for functional apo-carotenoids(Reference Cooperstone, Novotny, Riedl, Cichon, Francis, Curley, Schwartz and Harrison154). This highlights cooking and food processing as important cultural achievement for generating bioactive derivatives for enabling a healthy and well-functioning human organism(Reference Rosati155).

However, carotenoids are generally considered as lipid precursors (mainly for bioactive vitamin A / retinoids) in the diet, while their complex and multi-step metabolic pathways and the relationship with health beneficial effects are still poorly understood. In this review, we summarised all available relevant information focusing on the human organism with implication of mechanistic results from further in vitro to in vivo experiments. Unfortunately, these experimental results are difficult to generalise to humans owing to the non-similar nutri-kinetics pattern of carotenoids(Reference Lee, Boileau, Boileau, Williams, Swanson, Heintz and Erdman156) and different eating behaviour in humans compared with the pure vegetarian dietary pattern of rodents, which are frequently used as experimental animal models.

Conclusions

As a cornerstone, we suggest that, besides benchmark concentrations for carotenoids, retinoids should also be considered, including both ‘normal’ and deficiency threshold ranges. These ranges should correlate with well-defined and established nuclear hormone receptor signalling cascade markers, disease markers, prognostic early markers of diseases and markers of impairments of physiologically important functions based on novel ‘omics’ markers such as transcriptomics, lipidomics and proteomics, which are now frequently published for various target diseases(Reference Olivier, Asmis, Hawkins, Howard and Cox157). In the case of diseases and dysfunctions related to carotenoid and vitamin A deficiency, underlying molecular mechanisms such as RAR–RXR- / RXR-plus additional nuclear hormone receptor (NHR)-dysfunctional signalling(Reference Evans and Mangelsdorf22,Reference Desvergne25,Reference Szanto, Narkar, Shen, Uray, Davies and Nagy158) (i.e. signalling not associated with a healthy condition as present in various diseases of Western society) should also be considered.

On the basis of these two ranges, targeted supplementation strategies may be recommended to overcome deficiencies and reach and maintain ‘normal’ concentration ranges. A correlation between dietary intake, serum levels and bioactive carotenoid metabolites and further examination of RXR–RAR / RXR–NHR in an easily accessible compartment such as peripheral blood mononuclear cells (PBMCs), plus target genes of relevant diseases, are missing in carotenoid / retinoid nutritional research.

The basal benchmark concentration indicating a higher risk for chronic diseases appears to constitute a total carotenoid plasma / serum concentration <1·000 nM and should further focus on endogenous retinoids. The second benchmark concentration reflecting ‘normal’ carotenoid intake is average plasma / serum concentration of individual and total carotenoids indicating, and here defined as, a healthy varied diet. Such levels can then be translated into the intake of relevant food items rich in carotenoids, based on correlations between reported average intakes for β-carotene and lycopene with serum concentrations and considering intervention with carotenoid-rich foods(Reference Böhm, Borel and Corte-Real97).

In this review article, we summarised the current mechanisms of carotenoid metabolism including reference levels of bioactive carotenoid metabolites with relevance to the human organism. To summarise, elucidation of carotenoid-to-bioactive-metabolite metabolism is important to justify which biological-response pathway of carotenoids is enabled to elicit valuable beneficial effects. This is paramount in order to evaluate if there might be a problem in individual dietary intake of food enriched in specific carotenoids is present or if a genetic hereditary problem in metabolism of carotenoids to bioactive carotenoids based on genetic polymorphisms is the cause of disturbed occurrence of bioactive carotenoid metabolites.

Acknowledgements

This article is partly based upon work from the COST Action 13156, EUROCAROTEN (European network to advance carotenoid research and applications in agro-food and health, www.eurocaroten.eu), supported by COST (European Cooperation in Science and Technology). Opinions contained herein are those of the authors and do not necessarily represent the views of any institutions.

This article is not sponsored or funded by any agency or association, and has received support only from the EU-COST Action 13 156.

There are no conflicts of interest.

References

Yabuzaki, J (2017) Carotenoids Database: structures, chemical fingerprints and distribution among organisms. Database (Oxford) 2017, bax004.CrossRefGoogle ScholarPubMed
Rodriguez-Concepcion, M, Avalos, J, Bonet, ML, et al. (2018) A global perspective on carotenoids: metabolism, biotechnology, and benefits for nutrition and health. Prog Lipid Res 70, 6293.CrossRefGoogle ScholarPubMed
Felemban, A, Braguy, J, Zurbriggen, MD & Al-Babili, S (2019) Apocarotenoids involved in plant development and stress response. Front Plant Sci 10, 1168.CrossRefGoogle ScholarPubMed
Harrison, EH & Quadro, L (2018) Apocarotenoids: emerging roles in mammals. Annu Rev Nutr 38, 153172.CrossRefGoogle ScholarPubMed
Sluijs, I, Cadier, E, Beulens, JW, van der, AD, Spijkerman, AM & van der Schouw, YT (2015) Dietary intake of carotenoids and risk of type 2 diabetes. Nutr Metab Cardiovasc Dis 25, 376381.CrossRefGoogle ScholarPubMed
Zhou, H, Zhao, X, Johnson, EJ, et al. (2011) Serum carotenoids and risk of age-related macular degeneration in a Chinese population sample. Invest Ophthalmol Visual Sci 52, 43384344.CrossRefGoogle Scholar
Dulińska-Litewka, J, Hałubiec, P, Łazarczyk, A, Szafrański, O, Sharoni, Y, McCubrey, JA, Gąsiorkiewicz, B & Bohn, T (2021) Recent progress in discovering the role of carotenoids and metabolites in prostatic physiology and pathology – a review – part II: carotenoids in the human studies. Antioxidants (Basel, Switzerland) 10, 319.Google Scholar
Zhao, LG, Zhang, QL, Zheng, JL, Li, HL, Zhang, W, Tang, WG & Xiang, YB (2016) Dietary, circulating beta-carotene and risk of all-cause mortality: a meta-analysis from prospective studies. Sci Rep 6, 26983.CrossRefGoogle ScholarPubMed
Krinsky, NI & Johnson, EJ (2005) Carotenoid actions and their relation to health and disease. Mol Aspects Med 26, 459516.CrossRefGoogle ScholarPubMed
Bohn, T (2019) Carotenoids and markers of oxidative stress in human observational studies and intervention trials – implications for chronic diseases. Antioxidants 8, pii: E179.CrossRefGoogle Scholar
Bonet, ML, Canas, JA, Ribot, J & Palou, A (2016) Carotenoids in adipose tissue biology and obesity. Subcell Biochem 79, 377414.CrossRefGoogle ScholarPubMed
Rühl, R (2007) Effects of dietary retinoids and carotenoids on immune development. Proc Nutr Soc 66, 458469.CrossRefGoogle ScholarPubMed
Mounien, L, Tourniaire, F & Landrier, J-F (2019) Anti-obesity effect of carotenoids: direct impact on adipose tissue and adipose tissue-driven indirect effects. Nutrients 11, 1562.CrossRefGoogle ScholarPubMed
Amengual, J, Widjaja-Adhi, MA, Rodriguez-Santiago, S, Hessel, S, Golczak, M, Palczewski, K & von Lintig, J (2013) Two carotenoid oxygenases contribute to mammalian provitamin A metabolism. J Biol Chem 288, 3408134096.CrossRefGoogle ScholarPubMed
Linnewiel, K, Ernst, H, Caris-Veyrat, C, Ben-Dor, A, Kampf, A, Salman, H, Danilenko, M, Levy, J & Sharoni, Y (2009) Structure activity relationship of carotenoid derivatives in activation of the electrophile/antioxidant response element transcription system. Free Radic Biol Med 47, 659667.CrossRefGoogle ScholarPubMed
Linnewiel-Hermoni, K, Motro, Y, Miller, Y, Levy, J & Sharoni, Y (2014) Carotenoid derivatives inhibit nuclear factor kappa B activity in bone and cancer cells by targeting key thiol groups. Free Radic Biol Med 75, 105120.CrossRefGoogle ScholarPubMed
Nidhi, B, Sharavana, G, Ramaprasad, TR & Vallikannan, B (2015) Lutein derived fragments exhibit higher antioxidant and anti-inflammatory properties than lutein in lipopolysaccharide induced inflammation in rats. Food Funct 6, 450460.CrossRefGoogle ScholarPubMed
Farkhondeh, T & Samarghandian, S (2014) The effect of saffron (Crocus sativus L.) and its ingredients on the management of diabetes mellitus and dislipidemia. Afr J Pharm Pharmacol 8, 541549.Google Scholar
Bruzzone, S, Ameri, P, Briatore, L, et al. (2012) The plant hormone abscisic acid increases in human plasma after hyperglycemia and stimulates glucose consumption by adipocytes and myoblasts. FASEB J 26, 12511260.CrossRefGoogle ScholarPubMed
Aydemir, G, Kasiri, Y, Bartok, EM, Birta, E, Frohlich, K, Bohm, V, Mihaly, J & Rühl, R (2016) Lycopene supplementation restores vitamin A deficiency in mice and possesses thereby partial pro-vitamin A activity transmitted via RAR signaling. Mol Nutr Food Res 60, 24132420.CrossRefGoogle ScholarPubMed
Dingeo, G, Brito, A, Samouda, H, La Frano, MR & Bohn, T (2020) Phytochemicals as modifiers of gut microbial communities. Food Function 11, 84448471.CrossRefGoogle ScholarPubMed
Evans, RM & Mangelsdorf, DJ (2014) Nuclear receptors, RXR, and the big bang. Cell 157, 255266.CrossRefGoogle ScholarPubMed
Mangelsdorf, DJ, Thummel, C, Beato, M, et al. (1995) The nuclear receptor superfamily: the second decade. Cell 83, 835839.CrossRefGoogle ScholarPubMed
Balmer, JE & Blomhoff, R (2002) Gene expression regulation by retinoic acid. J Lipid Res 43, 17731808.CrossRefGoogle ScholarPubMed
Desvergne, B (2007) RXR: from partnership to leadership in metabolic regulations. Vitam Horm 75, 132.CrossRefGoogle ScholarPubMed
Tourniaire, F, Musinovic, H, Gouranton, E, et al. (2015) All-trans retinoic acid induces oxidative phosphorylation and mitochondria biogenesis in adipocytes. J Lipid Res 56, 11001109.CrossRefGoogle ScholarPubMed
Karkeni, E, Bonnet, L, Astier, J, Couturier, C, Dalifard, J, Tourniaire, F & Landrier, JF (2017) All-trans-retinoic acid represses chemokine expression in adipocytes and adipose tissue by inhibiting NF-κB signaling. J Nutr Biochem 42, 101107.CrossRefGoogle ScholarPubMed
Mangelsdorf, DJ, Ong, ES, Dyck, JA & Evans, RM (1990) Nuclear receptor that identifies a novel retinoic acid response pathway. Nature 345, 224229.CrossRefGoogle ScholarPubMed
Levin, AA, Sturzenbecker, LJ, Kazmer, S, et al. (1992) 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature 355, 359361.CrossRefGoogle ScholarPubMed
Heyman, RA, Mangelsdorf, DJ, Dyck, JA, Stein, RB, Eichele, G, Evans, RM & Thaller, C (1992) 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 68, 397406.CrossRefGoogle Scholar
Petkovich, M, Brand, NJ, Krust, A & Chambon, P (1987) A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature 330, 444450.CrossRefGoogle Scholar
Eroglu, A, Hruszkewycz, DP, dela Sena, C, et al. (2012) Naturally occurring eccentric cleavage products of provitamin A beta-carotene function as antagonists of retinoic acid receptors. J Biol Chem 287, 1588615895.CrossRefGoogle ScholarPubMed
Krezel, W, Rühl, R & de Lera, AR (2019) Alternative retinoid X receptor (RXR) ligands. Mol Cell Endocrinol 491, 110436.CrossRefGoogle ScholarPubMed
Schierle, S & Merk, D (2019) Therapeutic modulation of retinoid X receptors – SAR and therapeutic potential of RXR ligands and recent patents. Expert Opin Ther Pat 29, 605621.CrossRefGoogle ScholarPubMed
Schmidt, CK, Brouwer, A & Nau, H (2003) Chromatographic analysis of endogenous retinoids in tissues and serum. Anal Biochem 315, 3648.CrossRefGoogle ScholarPubMed
de Lera, AR, Krezel, W & Rühl, R (2016) An endogenous mammalian retinoid X receptor ligand, at last! ChemMedChem 11, 10271037.CrossRefGoogle ScholarPubMed
Rühl, R, Bub, A & Watzl, B (2008) Modulation of plasma all-trans retinoic acid concentrations by the consumption of carotenoid-rich vegetables. Nutrition 24, 12241226.CrossRefGoogle ScholarPubMed
Allenby, G, Bocquel, MT, Saunders, M, et al. (1993) Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci USA 90, 3034.CrossRefGoogle ScholarPubMed
Allenby, G, Janocha, R, Kazmer, S, Speck, J, Grippo, JF & Levin, AA (1994) Binding of 9-cis-retinoic acid and all-trans-retinoic acid to retinoic acid receptors alpha, beta, and gamma. Retinoic acid receptor gamma binds all-trans-retinoic acid preferentially over 9-cis-retinoic acid. J Biol Chem 269, 1668916695.CrossRefGoogle ScholarPubMed
dela Sena, C, Narayanasamy, S, Riedl, KM, Curley, RW Jr, Schwartz, SJ, Harrison, EH (2013) Substrate specificity of purified recombinant human beta-carotene 15,15′-oxygenase (BCO1). J Biol Chem 288, 3709437103.CrossRefGoogle Scholar
dela Sena, C, Sun, J, Narayanasamy, S, Riedl, KM, Yuan, Y, Curley, RW Jr, Schwartz, SJ & Harrison, EH (2016) Substrate specificity of purified recombinant chicken beta-carotene 9′,10′-oxygenase (BCO2). J Biol Chem 291, 1460914619.CrossRefGoogle Scholar
Barua, AB & Olson, JA (1986) Retinoyl beta-glucuronide: an endogenous compound of human blood. Am J Clin Nutr 43, 481485.CrossRefGoogle ScholarPubMed
Sass, JO, Forster, A, Bock, KW & Nau, H (1994) Glucuronidation and isomerization of all-trans- and 13-cis-retinoic acid by liver microsomes of phenobarbital- or 3-methylcholanthrene-treated rats. Biochem Pharmacol 47, 485492.CrossRefGoogle ScholarPubMed
Radominska, A, Little, JM, Lehman, PA, Samokyszyn, V, Rios, GR, King, CD, Green, MD & Tephly, TR (1997) Glucuronidation of retinoids by rat recombinant UDP: glucuronosyltransferase 1.1 (bilirubin UGT). Drug Metab Dispos 25, 889892.Google ScholarPubMed
Amengual, J, Lobo, GP, Golczak, M, Li, HN, Klimova, T, Hoppel, CL, Wyss, A, Palczewski, K & von Lintig, J (2011) A mitochondrial enzyme degrades carotenoids and protects against oxidative stress. FASEB J 25, 948959.CrossRefGoogle ScholarPubMed
von Lintig, J & Vogt, K (2000) Filling the gap in vitamin A research. Molecular identification of an enzyme cleaving beta-carotene to retinal. J Biol Chem 275, 1191511920.CrossRefGoogle ScholarPubMed
Kiefer, C, Hessel, S, Lampert, JM, Vogt, K, Lederer, MO, Breithaupt, DE & von Lintig, J (2001) Identification and characterization of a mammalian enzyme catalyzing the asymmetric oxidative cleavage of provitamin A. J Biol Chem 276, 1411014116.CrossRefGoogle ScholarPubMed
Caris-Veyrat, C, Schmid, A, Carail, M & Böhm, V (2003) Cleavage products of lycopene produced by in vitro oxidations: characterization and mechanisms of formation. J Agric Food Chem 51, 73187325.CrossRefGoogle ScholarPubMed
Bohn, T, Desmarchelier, C, El, SN, Keijer, J, van Schothorst, E, Rühl, R & Borel, P (2019) beta-Carotene in the human body: metabolic bioactivation pathways – from digestion to tissue distribution and excretion. Proc Nutr Soc 78, 6887.CrossRefGoogle ScholarPubMed
Bohn, T, Desmarchelier, C, Dragsted, LO, Nielsen, CS, Stahl, W, Rühl, R, Keijer, J & Borel, P (2017) Host-related factors explaining interindividual variability of carotenoid bioavailability and tissue concentrations in humans. Mol Nutr Food Res 61, 1600685.CrossRefGoogle ScholarPubMed
Bohn, T, Bonet, ML, Borel, P, et al. (2021) Mechanistic aspects of carotenoid health benefits – where are we now? Nutr Res Rev 34, 276302.CrossRefGoogle ScholarPubMed
Rubin, LP, Ross, AC, Stephensen, CB, Bohn, T & Tanumihardjo, SA (2017) Metabolic effects of inflammation on vitamin A and carotenoids in humans and animal models. Adv Nutr 8, 197212.CrossRefGoogle Scholar
Al Senaidy, AM (2009) Serum vitamin A and beta-carotene levels in children with asthma. J Asthma 46, 699702.CrossRefGoogle ScholarPubMed
Nogueira, C, Borges, F, Lameu, E, Franca, C, Rosa, CL & Ramalho, A (2015) Retinol, beta-carotene and oxidative stress in systemic inflammatory response syndrome. Rev Assoc Med Bras (1992) 61, 116120.CrossRefGoogle ScholarPubMed
Akhtar, S, Ahmed, A, Randhawa, MA, Atukorala, S, Arlappa, N, Ismail, T & Ali, Z (2013) Prevalence of vitamin A deficiency in South Asia: causes, outcomes, and possible remedies. J Health Popul Nutr 31, 413423.Google ScholarPubMed
EFSA Panel on Dietetic Products N, and Allergies (NDA), European Food Safety Authority (EFSA) (2015) Scientific opinion on detary reference values for vitamin A. EFSA J 13, 4028.CrossRefGoogle Scholar
Biehler, E, Alkerwi, A, Hoffmann, L, Krause, E, Guillaume, M, Lair, ML & Bohn, T (2012) Contribution of violaxanthin, neoxanthin, phytoene and phytofluene to total carotenoid intake: assessment in Luxembourg. J Food Comp Anal 25, 5665.CrossRefGoogle Scholar
Aage, S, Kiraly, N, Da Costa, K, Byberg, S, Bjerregaard-Andersen, M, Fisker, AB, Aaby, P & Benn, CS (2015) Neonatal vitamin A supplementation associated with increased atopy in girls. Allergy 70, 985994.CrossRefGoogle ScholarPubMed
Rühl, R (2013) Non-pro-vitamin A and pro-vitamin A carotenoids in atopy development. Int Arch Allergy Immunol 161, 99115.CrossRefGoogle ScholarPubMed
Milner, JD, Stein, DM, McCarter, R & Moon, RY (2004) Early infant multivitamin supplementation is associated with increased risk for food allergy and asthma. Pediatrics 114, 2732.CrossRefGoogle ScholarPubMed
Michaelsson, K, Lithell, H, Vessby, B & Melhus, H (2003) Serum retinol levels and the risk of fracture. N Engl J Med 348, 287294.CrossRefGoogle ScholarPubMed
Ruiz-Castell, M, Le Coroller, G, Landrier, JF, Kerkour, D, Weber, B, Fagherazzi, G, Appenzeller, BMR, Vaillant, M & Bohn, T (2020) Micronutrients and markers of oxidative stress and inflammation related to cardiometabolic health: results from the EHES-LUX study. Nutrients 13, 5.CrossRefGoogle ScholarPubMed
Crandall, C (2004) Vitamin A intake and osteoporosis: a clinical review. J Womens Health (Larchmt) 13, 939953.CrossRefGoogle ScholarPubMed
Mihaly, J, Gericke, J, Lucas, R, de Lera, AR, Alvarez, S, Torocsik, D & Rühl, R (2016) TSLP expression in the skin is mediated via RARgamma-RXR pathways. Immunobiology 221, 161165.CrossRefGoogle ScholarPubMed
Rühl, R, Taner, C, Schweigert, FJ, Wahn, U & Gruber, C (2010) Serum carotenoids and atopy among children of different ethnic origin living in Germany. Pediatr Allergy Immunol 21, 10721075.CrossRefGoogle ScholarPubMed
Gericke, J, Ittensohn, J, Mihaly, J, Dubrac, S & Rühl, R (2013) Allergen-induced dermatitis causes alterations in cutaneous retinoid-mediated signaling in mice. PLoS ONE 8, e71244.CrossRefGoogle ScholarPubMed
Gruber, C, Taner, C, Mihaly, J, Matricardi, PM, Wahn, U & Rühl, R (2012) Serum retinoic acid and atopy among children of different ethnic origin living in Germany. J Pediatr Gastroenterol Nutr 54, 558560.CrossRefGoogle ScholarPubMed
Wei, S, Kozono, S, Kats, L, et al. (2015) Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nat Med 21, 457466.CrossRefGoogle ScholarPubMed
Connolly, RM, Nguyen, NK & Sukumar, S (2013) Molecular pathways: current role and future directions of the retinoic acid pathway in cancer prevention and treatment. Clin Cancer Res 19, 16511659.CrossRefGoogle ScholarPubMed
Tan, X, Sande, JL, Pufnock, JS, Blattman, JN & Greenberg, PD (2011) Retinoic acid as a vaccine adjuvant enhances CD8+ T cell response and mucosal protection from viral challenge. J Virol 85, 83168327.CrossRefGoogle ScholarPubMed
Saiag, P, Pavlovic, M, Clerici, T, Feauveau, V, Nicolas, JC, Emile, D & Chastang, C (1998) Treatment of early AIDS-related Kaposi’s sarcoma with oral all-trans-retinoic acid: results of a sequential non-randomized phase II trial. Kaposi’s Sarcoma ANRS Study Group. Agence Nationale de Recherches sur le SIDA. Aids 12, 21692176.CrossRefGoogle Scholar
Tzimas, G & Nau, H (2001) The role of metabolism and toxicokinetics in retinoid teratogenesis. Curr Pharm 7(9), 803831.CrossRefGoogle ScholarPubMed
David, M, Hodak, E & Lowe, NJ (1988) Adverse effects of retinoids. Med Toxicol Adverse Drug Exp 3, 273288.Google ScholarPubMed
Govind Babu, K, Lokesh, KN, Suresh Babu, MC & Bhat, GR (2016) Acute coronary syndrome manifesting as an adverse effect of all-trans-retinoic acid in acute promyelocytic leukemia: a case report with review of the literature and a spotlight on management. Case Rep Oncol Med 2016, 9.Google Scholar
Henning, P, Conaway, HH & Lerner, UH (2015) Retinoid receptors in bone and their role in bone remodeling. Front Endocrinol (Lausanne) 6, 31.CrossRefGoogle ScholarPubMed
Trasino, SE & Gudas, LJ (2015) Vitamin A: a missing link in diabetes? Diabetes Manag (Lond) 5, 359367.CrossRefGoogle ScholarPubMed
Rühl, R, Garcia, A, Schweigert, FJ & Worm, M (2004) Modulation of cytokine production by low and high retinoid diets in ovalbumin-sensitized mice. Int J Vitam Nutr Res 74, 279284.CrossRefGoogle ScholarPubMed
Wansley, DL, Yin, Y & Prussin, C (2013) The retinoic acid receptor-alpha modulators ATRA and Ro415253 reciprocally regulate human IL-5+ Th2 cell proliferation and cytokine expression. Clin Mol Allergy 11, 4.CrossRefGoogle ScholarPubMed
Khachik, F, Spangler, CJ, Smith, JC Jr, Canfield, LM, Steck, A & Pfander, H (1997) Identification, quantification, and relative concentrations of carotenoids and their metabolites in human milk and serum. Anal Chem 69, 18731881.CrossRefGoogle ScholarPubMed
Britton, G, Liaaen-Jensen, S & Pfander, H (2008) Carotenoids handbook. Basel: Birkhäuser.CrossRefGoogle Scholar
Kopec, RE, Caris-Veyrat, C, Nowicki, M, Gleize, B, Desmarchelier, C & Borel, P (2018) Production of asymmetric oxidative metabolites of ¹3C β-carotene during digestion in the gastrointestinal lumen of healthy men. Am J Clin Nutr 108, 803813.CrossRefGoogle ScholarPubMed
Sy, C, Dangles, O, Borel, P & Caris-Veyrat, C (2013) Iron-induced oxidation of (all-E)-beta-carotene under model gastric conditions: kinetics, products, and mechanism. Free Radical Biol Med 63, 195206.CrossRefGoogle ScholarPubMed
Ferruzzi, MG, Lumpkin, JL, Schwartz, SJ & Failla, M (2006) Digestive stability, micellarization, and uptake of beta-carotene isomers by Caco-2 human intestinal cells. J Agric Food Chem 54, 27802785.CrossRefGoogle ScholarPubMed
Granado-Lorencio, F, Olmedilla-Alonso, B, Herrero-Barbudo, C, Perez-Sacristan, B, Blanco-Navarro, I & Blazquez-Garcia, S (2007) Comparative in vitro bioaccessibility of carotenoids from relevant contributors to carotenoid intake. J Agric Food Chem 55, 63876394.CrossRefGoogle ScholarPubMed
Richelle, M, Sanchez, B, Tavazzi, I, Lambelet, P, Bortlik, K & Williamson, G (2010) Lycopene isomerisation takes place within enterocytes during absorption in human subjects. Br J Nutr 103, 18001807.CrossRefGoogle ScholarPubMed
Eroglu, A & Harrison, EH (2013) Carotenoid metabolism in mammals, including man: formation, occurrence, and function of apocarotenoids. J Lipid Res 54, 17191730.CrossRefGoogle ScholarPubMed
Harrison, EH, dela Sena, C, Eroglu, A & Fleshman, MK (2012) The formation, occurrence, and function of beta-apocarotenoids: beta-carotene metabolites that may modulate nuclear receptor signaling. Am J Clin Nutr 96, 1189s1192s.CrossRefGoogle ScholarPubMed
Bandara, S, Thomas, LD, Ramkumar, S, Khadka, N, Kiser, PD, Golczak, M & von Lintig, J (2021) The structural and biochemical basis of apocarotenoid processing by β-carotene oxygenase-2. ACS Chem Biol 16, 480490.CrossRefGoogle ScholarPubMed
Amengual, J, Gouranton, E, van Helden, YG, et al. (2011) Beta-carotene reduces body adiposity of mice via BCMO1. PLoS ONE 6, e20644.CrossRefGoogle ScholarPubMed
Kim, YS & Oh, DK (2010) Biotransformation of carotenoids to retinal by carotenoid 15,15′-oxygenase. Appl Microbiol Biotechnol 88, 807816.CrossRefGoogle ScholarPubMed
Harrison, EH (2022) Carotenoids, β-apocarotenoids, and retinoids: the long and the short of it. Nutrients 14, 1411.CrossRefGoogle Scholar
Böhm, V, Lietz, G, Olmedilla-Alonso, B, et al. (2021) From carotenoid intake to carotenoid blood and tissue concentrations – implications for dietary intake recommendations. Nutr Rev 79, 544573.CrossRefGoogle ScholarPubMed
Ho, CC, de Moura, FF, Kim, S-H & Clifford, AJ (2007) Excentral cleavage of β-carotene in vivo in a healthy man. Am J Clin Nutr 85, 770777.CrossRefGoogle Scholar
Cooperstone, JL, Riedl, KM, Cichon, MJ, Francis, DM, Curley, RW, Schwartz, SJ, Novotny, JA & Harrison, EH (2017) Carotenoids and apo-carotenoids in human plasma after continued consumption of high β-carotene or high lycopene tomato juice. FASEB J 31 (1 Supplement), 635.613.Google Scholar
Sommerburg, O, Langhans, CD, Arnhold, J, et al. (2003) Beta-carotene cleavage products after oxidation mediated by hypochlorous acid – a model for neutrophil-derived degradation. Free Radic Biol Med 35, 14801490.CrossRefGoogle Scholar
von Lintig, J & Wyss, A (2001) Molecular analysis of vitamin A formation: cloning and characterization of beta-carotene 15,15′-dioxygenases. Arch Biochem Biophys 385, 4752.CrossRefGoogle Scholar
Böhm, V, Borel, P, Corte-Real, J, et al. (2021) From carotenoid intake to carotenoid blood and tissue concentrations – implications for dietary intake recommendations. Nutr Rev 79, 544573.CrossRefGoogle ScholarPubMed
Horst, RL, Reinhardt, TA, Goff, JP, Nonnecke, BJ, Gambhir, VK, Fiorella, PD & Napoli, JL (1995) Identification of 9-cis,13-cis-retinoic acid as a major circulating retinoid in plasma. Biochemistry 34, 12031209.CrossRefGoogle Scholar
Kane, MA, Chen, N, Sparks, S & Napoli, JL (2005) Quantification of endogenous retinoic acid in limited biological samples by LC/MS/MS. Biochem J 388, 363369.CrossRefGoogle ScholarPubMed
Sass, JO & Nau, H (1994) Single-run analysis of isomers of retinoyl-beta-d-glucuronide and retinoic acid by reversed-phase high-performance liquid chromatography. J Chromatogr A 685, 182188.CrossRefGoogle ScholarPubMed
Wolf, G (2006) Is 9-cis-retinoic acid the endogenous ligand for the retinoic acid-X receptor? Nutr Rev 64, 532538.CrossRefGoogle Scholar
Rühl, R, Krzyzosiak, A, Niewiadomska-Cimicka, A, et al. (2015) 9-cis-13,14-dihydroretinoic acid is an endogenous retinoid acting as RXR ligand in mice. PLoS Genet 11, e1005213.CrossRefGoogle ScholarPubMed
Palczewski, K (2012) Chemistry and biology of vision. J Biol Chem 287, 16121619.CrossRefGoogle ScholarPubMed
von Lintig, J, Moon, J & Babino, D (2021) Molecular components affecting ocular carotenoid and retinoid homeostasis. Prog Retin Eye Res 80, 100864.CrossRefGoogle ScholarPubMed
Watzl, B, Bub, A, Brandstetter, BR & Rechkemmer, G (1999) Modulation of human T-lymphocyte functions by the consumption of carotenoid-rich vegetables. Br J Nutr 82, 383389.CrossRefGoogle ScholarPubMed
Watzl, B, Bub, A, Briviba, K & Rechkemmer, G (2003) Supplementation of a low-carotenoid diet with tomato or carrot juice modulates immune functions in healthy men. Ann Nutr Metab 47, 255261.CrossRefGoogle ScholarPubMed
Underwood, BA (1994) Was the “anti-infective” vitamin misnamed? Nutr Rev 52, 140143.CrossRefGoogle Scholar
Lee, LM, Leung, CY, Tang, WW, et al. (2012) A paradoxical teratogenic mechanism for retinoic acid. Proc Natl Acad Sci USA 109, 1366813673.CrossRefGoogle ScholarPubMed
Wang, XD, Liu, C, Bronson, RT, Smith, DE, Krinsky, NI & Russell, M (1999) Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke. J Natl Cancer Inst 91, 6066.CrossRefGoogle ScholarPubMed
Lotan, R (1999) Lung cancer promotion by beta-carotene and tobacco smoke: relationship to suppression of retinoic acid receptor-beta and increased activator protein-1? J Natl Cancer Inst 91, 79.CrossRefGoogle Scholar
Moise, AR, Kuksa, V, Imanishi, Y & Palczewski, K (2004) Identification of all-trans-retinol:all-trans-13,14-dihydroretinol saturase. J Biol Chem 279, 5023050242.CrossRefGoogle ScholarPubMed
Moise, AR, Alvarez, S, Dominguez, M, et al. (2009) Activation of retinoic acid receptors by dihydroretinoids. Mol Pharmacol 76, 12281237.CrossRefGoogle ScholarPubMed
Bazhin, AV, Bleul, T, de Lera, AR, Werner, J & Rühl, R (2016) Relationship between all-trans-13,14-dihydro retinoic acid and pancreatic adenocarcinoma. Pancreas 45, e29e31.CrossRefGoogle ScholarPubMed
Lucas, R, Szklenar, M, Mihály, J, Szegedi, A, Töröcsik, D & Rühl, R (2022) Plasma levels of bioactive vitamin D and A5 ligands positively correlate with clinical atopic dermatitis markers. Dermatology 238, 10761083.CrossRefGoogle ScholarPubMed
Sani, BP, Venepally, PR & Levin, AA (1997) Didehydroretinoic acid: retinoid receptor-mediated transcriptional activation and binding properties. Biochem Pharmacol 53, 10491053.CrossRefGoogle ScholarPubMed
Rühl, R, Krezel, W & de Lera, AR (2018) 9-cis-13,14-dihydroretinoic acid, a new endogenous mammalian ligand of retinoid X receptor and the active ligand of a potential new vitamin A category: vitamin A5. Nutr Rev 76, 929941.CrossRefGoogle Scholar
Krężel, W, Rivas, A, Szklenar, M, Ciancia, M, Alvarez, R, de Lera, AR & Rühl, R (2021) Vitamin A5/X, a new food to lipid hormone concept for a nutritional ligand to control RXR-mediated signaling. Nutrients 13, 925.CrossRefGoogle ScholarPubMed
Bohn, T, Hellmann-Regen, J, de Lera, Á R, Böhm, V & Rühl, R (2022) Human nutritional relevance and suggested nutritional guidelines for vitamin A5/X and provitamin A5/X (submitted for publication).CrossRefGoogle Scholar
Khachik, F, Carvalho, L, Bernstein, PS, Muir, GJ, Zhao, DY & Katz, NB (2002) Chemistry, distribution, and metabolism of tomato carotenoids and their impact on human health. Exp Biol Med (Maywood) 227, 845851.CrossRefGoogle ScholarPubMed
van den Berg, H (1998) Effect of lutein on beta-carotene absorption and cleavage. Int J Vitam Nutr Res 68, 360365.Google ScholarPubMed
van den Berg, H & van Vliet, T (1998) Effect of simultaneous, single oral doses of beta-carotene with lutein or lycopene on the beta-carotene and retinyl ester responses in the triacylglycerol-rich lipoprotein fraction of men. Am J Clin Nutr 68, 8289.CrossRefGoogle ScholarPubMed
Caris-Veyrat, C, Garcia, AL, Reynaud, E, Lucas, R, Aydemir, G & Rühl, R (2016) Lycopene-induced nuclear hormone receptor signalling in inflammation and lipid metabolism via still unknown endogenous apo-10′-lycopenoids. Int J Vitam Nutr Res 86, 6270.CrossRefGoogle ScholarPubMed
Ford, NA & Erdman, JW Jr (2012) Are lycopene metabolites metabolically active? Acta Biochim Pol 59, 14.CrossRefGoogle Scholar
Aydemir, G, Kasiri, Y, Birta, E, Beke, G, Garcia, AL, Bartok, EM & Rühl, R (2013) Lycopene-derived bioactive retinoic acid receptors/retinoid-X receptors-activating metabolites may be relevant for lycopene’s anti-cancer potential. Mol Nutr Food Res 57, 739747.CrossRefGoogle ScholarPubMed
Kopec, RE, Riedl, KM, Harrison, EH, Curley, RW Jr, Hruszkewycz, DP, Clinton, SK & Schwartz, SJ (2010) Identification and quantification of apo-lycopenals in fruits, vegetables, and human plasma. J Agric Food Chem 58, 32903296.CrossRefGoogle ScholarPubMed
Ferreira, AL, Yeum, KJ, Russell, RM, Krinsky, NI & Tang, G (2003) Enzymatic and oxidative metabolites of lycopene. J Nutr Biochem 14, 531540.Google ScholarPubMed
Reynaud, E, Aydemir, G, Rühl, R, Dangles, O & Caris-Veyrat, C (2011) Organic synthesis of new putative lycopene metabolites and preliminary investigation of their cell-signaling effects. J Agric Food Chem 59, 14571463.CrossRefGoogle ScholarPubMed
Lindshield, BL, Canene-Adams, K & Erdman, JW Jr (2007) Lycopenoids: are lycopene metabolites bioactive? Arch Biochem Biophys 458, 136140.CrossRefGoogle Scholar
Wang, XD (2012) Lycopene metabolism and its biological significance. Am J Clin Nutr 96, 1214s1222s.CrossRefGoogle ScholarPubMed
Gouranton, E, Aydemir, G, Reynaud, E, et al. (2011) Apo-10’-lycopenoic acid impacts adipose tissue biology via the retinoic acid receptors. Biochim Biophys Acta 1811, 11051114.CrossRefGoogle Scholar
Hu, KQ, Liu, C, Ernst, H, Krinsky, NI, Russell, RM & Wang, XD (2006) The biochemical characterization of ferret carotene-9′,10′-monooxygenase catalyzing cleavage of carotenoids in vitro and in vivo. J Biol Chem 281, 1932719338.CrossRefGoogle ScholarPubMed
Gajic, M, Zaripheh, S, Sun, F & Erdman, JW Jr (2006) Apo-8′-lycopenal and apo-12′-lycopenal are metabolic products of lycopene in rat liver. J Nutr 136, 15521557.CrossRefGoogle Scholar
Moran, NE, Thomas-Ahner, JM, Fleming, JL, et al. (2019) Single nucleotide polymorphisms in beta-carotene oxygenase 1 are associated with plasma lycopene responses to a tomato-soy juice intervention in men with prostate cancer. J Nutr 149, 381397.CrossRefGoogle ScholarPubMed
Aydemir, G, Carlsen, H, Blomhoff, R & Rühl, R (2012) Lycopene induces retinoic acid receptor transcriptional activation in mice. Mol Nutr Food Res 56, 702712.CrossRefGoogle ScholarPubMed
Ben-Dor, A, Nahum, A, Danilenko, M, et al. (2001) Effects of acyclo-retinoic acid and lycopene on activation of the retinoic acid receptor and proliferation of mammary cancer cells. Arch Biochem Biophys 391, 295302.CrossRefGoogle ScholarPubMed
Ip, BC, Liu, C, Lichtenstein, AH, von Lintig, J & Wang, XD (2015) Lycopene and apo-10′-lycopenoic acid have differential mechanisms of protection against hepatic steatosis in beta-carotene-9′,10′-oxygenase knockout male mice. J Nutr 145, 268276.CrossRefGoogle ScholarPubMed
Rühl, R (2009) Retinoids, vitamin A and pro-vitamin A carotenoids. Regulation of the immune system and allergies. Pharm Unserer Zeit 38, 126131.CrossRefGoogle ScholarPubMed
Muller, H, Bub, A, Watzl, B & Rechkemmer, G (1999) Plasma concentrations of carotenoids in healthy volunteers after intervention with carotenoid-rich foods. Eur J Nutr 38, 3544.Google ScholarPubMed
Rühl, R, Hanel, A, Garcia, AL, Dahten, A, Herz, U, Schweigert, FJ & Worm, M (2007) Role of vitamin A elimination or supplementation diets during postnatal development on the allergic sensitisation in mice. Mol Nutr Food Res 51, 11731181.CrossRefGoogle ScholarPubMed
Zunino, SJ, Storms, DH & Stephensen, CB (2007) Diets rich in polyphenols and vitamin A inhibit the development of type I autoimmune diabetes in nonobese diabetic mice. J Nutr 137, 12161221.CrossRefGoogle Scholar
Landrier, JF, Kasiri, E, Karkeni, E, et al. (2017) Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue. FASEB J 31, 203211.CrossRefGoogle ScholarPubMed
Rühl, R & Landrier, JF (2016) Dietary regulation of adiponectin by direct and indirect lipid activators of nuclear hormone receptors. Mol Nutr Food Res 60, 175184.CrossRefGoogle ScholarPubMed
Al-Babili, S & Bouwmeester, HJ (2015) Strigolactones, a novel carotenoid-derived plant hormone. Annu Rev Plant Biol 66, 161186.CrossRefGoogle ScholarPubMed
Jia, K-P, Baz, L & Al-Babili, S (2018) From carotenoids to strigolactones. JExB 69, 21892204.Google ScholarPubMed
Alder, A, Jamil, M, Marzorati, M, et al. (2012) The path from β-carotene to carlactone, a strigolactone-like plant hormone. Science 335, 13481351.CrossRefGoogle ScholarPubMed
Gomez-Roldan, V, Fermas, S, Brewer, PB, et al. (2008) Strigolactone inhibition of shoot branching. Nature 455, 189194.CrossRefGoogle ScholarPubMed
Casamassimi, A, Federico, A, Rienzo, M, Esposito, S & Ciccodicola, A (2017) Transcriptome profiling in human diseases: new advances and perspectives. Int J Mol Sci 18, 1652.CrossRefGoogle ScholarPubMed
Pedrotty, DM, Morley, MP & Cappola, TP (2012) Transcriptomic biomarkers of cardiovascular disease. Prog Cardiovasc Dis 55, 6469.CrossRefGoogle ScholarPubMed
Altucci, L, Leibowitz, MD, Ogilvie, KM, de Lera, AR & Gronemeyer, H (2007) RAR and RXR modulation in cancer and metabolic disease. Nat Rev Drug Discov 6, 793810.CrossRefGoogle ScholarPubMed
Jenab, M, Ferrari, P, Mazuir, M, et al. (2005) Variations in lycopene blood levels and tomato consumption across European countries based on the European Prospective Investigation into Cancer and Nutrition (EPIC) study. J Nutr 135, 2032s2036s.CrossRefGoogle ScholarPubMed
Xu, Y & Harvey, PJ (2019) Red light control of β-carotene isomerisation to 9-cis β-carotene and carotenoid accumulation in Dunaliella salina . Antioxidants (Basel, Switzerland) 8, 148.Google ScholarPubMed
Schieber, A & Carle, R (2005) Occurrence of carotenoid cis-isomers in food: technological, analytical, and nutritional implications. Trends Food Sci. Technol 16, 416422.CrossRefGoogle Scholar
Khoo, HE, Prasad, KN, Kong, KW, Jiang, Y & Ismail, A (2011) Carotenoids and their isomers: color pigments in fruits and vegetables. Molecules 16, 17101738.CrossRefGoogle ScholarPubMed
Cooperstone, JL, Novotny, JA, Riedl, KM, Cichon, MJ, Francis, DM, Curley, RW Jr, Schwartz, SJ & Harrison, EH (2018) Limited appearance of apocarotenoids is observed in plasma after consumption of tomato juices: a randomized human clinical trial. Am J Clin Nutr 108, 784792.CrossRefGoogle ScholarPubMed
Rosati, A (2018) The dietary practice coincided with increases in brain size, evidence suggests. Sci Am. https://www.scientificamerican.com/article/food-for-thought-was-cooking-a-pivotal-step-in-human-evolution/ (assessed July 15, 2022).Google Scholar
Lee, CM, Boileau, AC, Boileau, TW, Williams, AW, Swanson, KS, Heintz, KA & Erdman, JW Jr (1999) Review of animal models in carotenoid research. J Nutr 129, 22712277.CrossRefGoogle Scholar
Olivier, M, Asmis, R, Hawkins, GA, Howard, TD & Cox, LA (2019) The need for multi-omics biomarker signatures in precision medicine. Int J Mol Sci 20, 4781.CrossRefGoogle ScholarPubMed
Szanto, A, Narkar, V, Shen, Q, Uray, IP, Davies, PJ & Nagy, L (2004) Retinoid X receptors: X-ploring their (patho)physiological functions. Cell Death Differ, 11 (Suppl 2), S126S143.CrossRefGoogle ScholarPubMed
Al-Delaimy, WK, Slimani, N, Ferrari, P, et al. (2005) Plasma carotenoids as biomarkers of intake of fruits and vegetables: ecological-level correlations in the European Prospective Investigation into Cancer and Nutrition (EPIC). Eur J Clin Nutr 59, 13971408.CrossRefGoogle ScholarPubMed
Schierle, J, Bretzel, W, Bühler, I, Faccin, N, Hess, D, Steiner, K & Schüep, W (1997) Content and isomeric ratio of lycopene in food and human blood plasma. Food Chem 59, 459465.CrossRefGoogle Scholar
Fröhlich, K (2007) Lycopin-Isomere in Lebensmitteln und Humanplasma - Strukturaufklärung, antioxidative Aktivität, Gehalte und relative (E)-(Z)-Verhältnisse. Germany: Friedrich-Schiller-Universität Jena.Google Scholar
Chung, HY, Ferreira, AL, Epstein, S, Paiva, SA, Castaneda-Sceppa, C & Johnson, EJ (2009) Site-specific concentrations of carotenoids in adipose tissue: relations with dietary and serum carotenoid concentrations in healthy adults. Am J Clin Nutr 90, 533539.CrossRefGoogle ScholarPubMed
Alaluf, S, Heinrich, U, Stahl, W, Tronnier, H & Wiseman, S (2002) Dietary carotenoids contribute to normal human skin color and UV photosensitivity. J Nutr 132, 399403.CrossRefGoogle ScholarPubMed
Ermakov, IV, Sharifzadeh, M, Ermakova, M & Gellermann, W (2005) Resonance Raman detection of carotenoid antioxidants in living human tissue. J Biomed Opt 10, 064028.CrossRefGoogle ScholarPubMed
Ermakov, IV, Ermakova, MR, Bernstein, PS, Chan, GM & Gellermann, W (2013) Resonance Raman based skin carotenoid measurements in newborns and infants. J Biophotonics 6, 793802.CrossRefGoogle ScholarPubMed
Schmitz, HH, Poor, CL, Wellman, RB, Erdman, JW Jr (1991) Concentrations of selected carotenoids and vitamin A in human liver, kidney and lung tissue. J Nutr 121, 16131621.CrossRefGoogle Scholar
Vishwanathan, R, Kuchan, MJ, Sen, S & Johnson, EJ (2014) Lutein and preterm infants with decreased concentrations of brain carotenoids. J Pediatr Gastroenterol Nutr 59, 659665.CrossRefGoogle ScholarPubMed
Stahl, W, Schwarz, W, Sundquist, AR, & Sies, H (1992) cis-trans isomers of lycopene and beta-carotene in human serum and tissues. Arch Biochem Biophys 294, 173177.CrossRefGoogle ScholarPubMed
Pappalardo, G, Maiani, G, Mobarhan, S, et al. (1997) Plasma (carotenoids, retinol, alpha-tocopherol) and tissue (carotenoids) levels after supplementation with beta-carotene in subjects with precancerous and cancerous lesions of sigmoid colon. Eur J Clin Nutr 51, 661666.CrossRefGoogle ScholarPubMed
Gossage, CP, Deyhim, M, Yamini, S, Douglass, LW & Moser-Veillon, PB (2002) Carotenoid composition of human milk during the first month postpartum and the response to β-carotene supplementation. Am J Clin Nutr 76, 193197.CrossRefGoogle ScholarPubMed
Czeczuga-Semeniuk, E & Wolczynski, S (2008) Dietary carotenoids in normal and pathological tissues of corpus uteri. Folia Histochem Cytobiol 46, 283290.CrossRefGoogle ScholarPubMed
Clinton, SK, Emenhiser, C, Schwartz, SJ, Bostwick, DG, Williams, AW, Moore, BJ & Erdman, JW Jr (1996) cis-trans lycopene isomers, carotenoids, and retinol in the human prostate. Cancer Epidemiol Biomarkers Prev 5, 823833.Google Scholar
Mihaly, J, Gamlieli, A, Worm, M & Rühl, R (2011) Decreased retinoid concentration and retinoid signalling pathways in human atopic dermatitis. Exp Dermatol 20, 326330.CrossRefGoogle ScholarPubMed
Arnhold, T, Tzimas, G, Wittfoht, W, Plonait, S & Nau, H (1996) Identification of 9-cis-retinoic acid, 9,13-di-cis-retinoic acid, and 14-hydroxy-4,14-retro-retinol in human plasma after liver consumption. Life Sci 59, Pl169Pl177.CrossRefGoogle ScholarPubMed
Arnold, SL, Amory, JK, Walsh, TJ & Isoherranen, N (2012) A sensitive and specific method for measurement of multiple retinoids in human serum with UHPLC-MS/MS. J Lipid Res 53, 587598.CrossRefGoogle ScholarPubMed
Bleul, T, Rühl, R, Bulashevska, S, Karakhanova, S, Werner, J & Bazhin, AV (2015) Reduced retinoids and retinoid receptors’ expression in pancreatic cancer: a link to patient survival. Mol Carcinog 54, 870879.CrossRefGoogle ScholarPubMed
Aydemir, G, Domínguez, M, de Lera, AR, Mihaly, J, Törőcsik, D & Rühl, R (2019) Apo-14′-carotenoic acid is a novel endogenous and bioactive apo-carotenoid. Nutrients 11, 2084.CrossRefGoogle Scholar
Barua, AB & Sidell, N (2004) Retinoyl beta-glucuronide: a biologically active interesting retinoid. J Nutr 134, 286s289s.CrossRefGoogle ScholarPubMed
Vahlquist, A, Lee, JB, Michaelsson, G & Rollman, O (1982) Vitamin A in human skin: II concentrations of carotene, retinol and dehydroretinol in various components of normal skin. J Invest Dermatol 79, 9497.CrossRefGoogle ScholarPubMed
Wang, J, Yoo, HS, Obrochta, KM, Huang, P & Napoli, JL (2015) Quantitation of retinaldehyde in small biological samples using ultrahigh-performance liquid chromatography tandem mass spectrometry. Anal Biochem 484, 162168.CrossRefGoogle ScholarPubMed
Kane, MA, Folias, AE & Napoli, JL (2008) HPLC/UV quantitation of retinal, retinol, and retinyl esters in serum and tissues. Anal Biochem 378, 7179.CrossRefGoogle ScholarPubMed
Stahl, W, Hanusch, M & Sies, H (1996) 4-Oxo-retinoic acid is generated from its precursor canthaxanthin and enhances gap junctional communication in 10T1/2 cells. Adv Exp Med Biol 387, 121128.CrossRefGoogle Scholar
Figure 0

Fig. 1. Metabolic pathway starting from all-trans-β-carotene and all-trans-lycopene via (a) geometric isomerisation, (b) eccentric cleavage metabolism and (c) centric-cleavage mechanisms. Starting from food, towards transport and intermediate derivatives, nuclear hormone receptor activating ligands including further regulation of transcription and thereby major mediation of biological signalling of carotenoids and further deactivation / excretion metabolites. Arrows in the figure indicate potential and simplified metabolic pathways. Derivatives that were not conclusively identified to be present endogenously in humans were marked with a star (*) and represent derivatives which that were suggested as metabolites and identified in in vitro or in vivo experimental approaches. Additional derivatives, which were predicted based on analytical studies, were indicated by two starts (**). Abbreviations: AT: all-trans-, RAR: retinoic acid receptor, RXR: retinoid-X receptor.

Figure 1

Table 1. Concentrations of carotenoids in various tissues, all data in nM (nmol/kg or L), adapted from ref.(97)

Figure 2

Table 2. Levels of major carotenoid metabolites / retinoids in blood plasma / serum and tissues including molecular weight in Dalton (Da) and molecular formula of each retinoid