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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 ,
Angel R. de Lera ,
Jean-Francois Landrier  and
Ralph Rühl
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
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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.

Keywords

Apo-carotenoidsApo-lycopenoidsCleavage productsTissue concentrationsLiver
Type
Review Article
Information
Nutrition Research Reviews , Volume 36 , Issue 2 , December 2023 , pp. 498 - 511
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Copyright
© The Author(s), 2022. Published by Cambridge University Press on behalf of The Nutrition Society

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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, 62–93.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, 153–172.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, 376–381.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, 4338–4344.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, 459–516.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, 377–414.CrossRefGoogle ScholarPubMed
Rühl, R (2007) Effects of dietary retinoids and carotenoids on immune development. Proc Nutr Soc 66, 458–469.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, 34081–34096.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, 659–667.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, 105–120.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, 450–460.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, 541–549.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, 1251–1260.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, 2413–2420.CrossRefGoogle ScholarPubMed
Dingeo, G, Brito, A, Samouda, H, La Frano, MR & Bohn, T (2020) Phytochemicals as modifiers of gut microbial communities. Food Function 11, 8444–8471.CrossRefGoogle ScholarPubMed
Evans, RM & Mangelsdorf, DJ (2014) Nuclear receptors, RXR, and the big bang. Cell 157, 255–266.CrossRefGoogle ScholarPubMed
Mangelsdorf, DJ, Thummel, C, Beato, M, et al. (1995) The nuclear receptor superfamily: the second decade. Cell 83, 835–839.CrossRefGoogle ScholarPubMed
Balmer, JE & Blomhoff, R (2002) Gene expression regulation by retinoic acid. J Lipid Res 43, 1773–1808.CrossRefGoogle ScholarPubMed
Desvergne, B (2007) RXR: from partnership to leadership in metabolic regulations. Vitam Horm 75, 1–32.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, 1100–1109.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, 101–107.CrossRefGoogle ScholarPubMed
Mangelsdorf, DJ, Ong, ES, Dyck, JA & Evans, RM (1990) Nuclear receptor that identifies a novel retinoic acid response pathway. Nature 345, 224–229.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, 359–361.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, 397–406.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, 444–450.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, 15886–15895.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, 605–621.CrossRefGoogle ScholarPubMed
Schmidt, CK, Brouwer, A & Nau, H (2003) Chromatographic analysis of endogenous retinoids in tissues and serum. Anal Biochem 315, 36–48.CrossRefGoogle ScholarPubMed
de Lera, AR, Krezel, W & Rühl, R (2016) An endogenous mammalian retinoid X receptor ligand, at last! ChemMedChem 11, 1027–1037.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, 1224–1226.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, 30–34.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, 16689–16695.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, 37094–37103.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, 14609–14619.CrossRefGoogle Scholar
Barua, AB & Olson, JA (1986) Retinoyl beta-glucuronide: an endogenous compound of human blood. Am J Clin Nutr 43, 481–485.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, 485–492.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, 889–892.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, 948–959.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, 11915–11920.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, 14110–14116.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, 7318–7325.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, 68–87.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, 276–302.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, 197–212.CrossRefGoogle Scholar
Al Senaidy, AM (2009) Serum vitamin A and beta-carotene levels in children with asthma. J Asthma 46, 699–702.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, 116–120.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, 413–423.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, 56–65.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, 985–994.CrossRefGoogle ScholarPubMed
Rühl, R (2013) Non-pro-vitamin A and pro-vitamin A carotenoids in atopy development. Int Arch Allergy Immunol 161, 99–115.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, 27–32.CrossRefGoogle ScholarPubMed
Michaelsson, K, Lithell, H, Vessby, B & Melhus, H (2003) Serum retinol levels and the risk of fracture. N Engl J Med 348, 287–294.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, 939–953.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, 161–165.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, 1072–1075.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, 558–560.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, 457–466.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, 1651–1659.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, 8316–8327.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, 2169–2176.CrossRefGoogle Scholar
Tzimas, G & Nau, H (2001) The role of metabolism and toxicokinetics in retinoid teratogenesis. Curr Pharm 7(9), 803–831.CrossRefGoogle ScholarPubMed
David, M, Hodak, E & Lowe, NJ (1988) Adverse effects of retinoids. Med Toxicol Adverse Drug Exp 3, 273–288.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, 359–367.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, 279–284.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, 1873–1881.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, 803–813.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, 195–206.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, 2780–2785.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, 6387–6394.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, 1800–1807.CrossRefGoogle ScholarPubMed
Eroglu, A & Harrison, EH (2013) Carotenoid metabolism in mammals, including man: formation, occurrence, and function of apocarotenoids. J Lipid Res 54, 1719–1730.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, 1189s–1192s.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, 480–490.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, 807–816.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, 544–573.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, 770–777.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, 1480–1490.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, 47–52.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, 544–573.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, 1203–1209.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, 363–369.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, 182–188.CrossRefGoogle ScholarPubMed
Wolf, G (2006) Is 9-cis-retinoic acid the endogenous ligand for the retinoic acid-X receptor? Nutr Rev 64, 532–538.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, 1612–1619.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, 383–389.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, 255–261.CrossRefGoogle ScholarPubMed
Underwood, BA (1994) Was the “anti-infective” vitamin misnamed? Nutr Rev 52, 140–143.CrossRefGoogle Scholar
Lee, LM, Leung, CY, Tang, WW, et al. (2012) A paradoxical teratogenic mechanism for retinoic acid. Proc Natl Acad Sci USA 109, 13668–13673.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, 60–66.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, 7–9.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, 50230–50242.CrossRefGoogle ScholarPubMed
Moise, AR, Alvarez, S, Dominguez, M, et al. (2009) Activation of retinoic acid receptors by dihydroretinoids. Mol Pharmacol 76, 1228–1237.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, e29–e31.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, 1076–1083.CrossRefGoogle ScholarPubMed
Sani, BP, Venepally, PR & Levin, AA (1997) Didehydroretinoic acid: retinoid receptor-mediated transcriptional activation and binding properties. Biochem Pharmacol 53, 1049–1053.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, 929–941.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, 845–851.CrossRefGoogle ScholarPubMed
van den Berg, H (1998) Effect of lutein on beta-carotene absorption and cleavage. Int J Vitam Nutr Res 68, 360–365.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, 82–89.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, 62–70.CrossRefGoogle ScholarPubMed
Ford, NA & Erdman, JW Jr (2012) Are lycopene metabolites metabolically active? Acta Biochim Pol 59, 1–4.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, 739–747.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, 3290–3296.CrossRefGoogle ScholarPubMed
Ferreira, AL, Yeum, KJ, Russell, RM, Krinsky, NI & Tang, G (2003) Enzymatic and oxidative metabolites of lycopene. J Nutr Biochem 14, 531–540.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, 1457–1463.CrossRefGoogle ScholarPubMed
Lindshield, BL, Canene-Adams, K & Erdman, JW Jr (2007) Lycopenoids: are lycopene metabolites bioactive? Arch Biochem Biophys 458, 136–140.CrossRefGoogle Scholar
Wang, XD (2012) Lycopene metabolism and its biological significance. Am J Clin Nutr 96, 1214s–1222s.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, 1105–1114.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, 19327–19338.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, 1552–1557.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, 381–397.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, 702–712.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, 295–302.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, 268–276.CrossRefGoogle ScholarPubMed
Rühl, R (2009) Retinoids, vitamin A and pro-vitamin A carotenoids. Regulation of the immune system and allergies. Pharm Unserer Zeit 38, 126–131.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, 35–44.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, 1173–1181.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, 1216–1221.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, 203–211.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, 175–184.CrossRefGoogle ScholarPubMed
Al-Babili, S & Bouwmeester, HJ (2015) Strigolactones, a novel carotenoid-derived plant hormone. Annu Rev Plant Biol 66, 161–186.CrossRefGoogle ScholarPubMed
Jia, K-P, Baz, L & Al-Babili, S (2018) From carotenoids to strigolactones. JExB 69, 2189–2204.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, 1348–1351.CrossRefGoogle ScholarPubMed
Gomez-Roldan, V, Fermas, S, Brewer, PB, et al. (2008) Strigolactone inhibition of shoot branching. Nature 455, 189–194.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, 64–69.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, 793–810.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, 2032s–2036s.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, 416–422.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, 1710–1738.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, 784–792.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, 2271–2277.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), S126–S143.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, 1397–1408.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, 459–465.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, 533–539.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, 399–403.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, 793–802.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, 1613–1621.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, 659–665.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, 173–177.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, 661–666.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, 193–197.CrossRefGoogle ScholarPubMed
Czeczuga-Semeniuk, E & Wolczynski, S (2008) Dietary carotenoids in normal and pathological tissues of corpus uteri. Folia Histochem Cytobiol 46, 283–290.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, 823–833.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, 326–330.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, Pl169– Pl177.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, 587–598.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, 870–879.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, 286s–289s.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, 94–97.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, 162–168.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, 71–79.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, 121–128.CrossRefGoogle Scholar