Title: Carotenoid metabolism in mammals, including man: formation, occurrence, and function of apocarotenoids
Abstract: Vitamin A was recognized as an essential nutrient 100 years ago. In the 1930s, it became clear that dietary β-carotene was cleaved at its central double to yield vitamin A (retinal or β-apo-15′-carotenal). Thus a great deal of research has focused on the central cleavage of provitamin A carotenoids to form vitamin A (retinoids). The mechanisms of formation and the physiological role(s) of noncentral (eccentric) cleavage of both provitamin A carotenoids and nonprovitamin A carotenoids has been less clear. It is becoming apparent that the apocarotenoids exert unique biological activities themselves. These compounds are found in the diet and thus may be absorbed in the intestine, or they may form from enzymatic or nonenzymatic cleavage of the parent carotenoids. The mechanism of action of apocarotenoids in mammals is not fully worked out. However, as detailed in this review, they have profound effects on gene expression and work, at least in part, through the modulation of ligand-activated nuclear receptors. Understanding the interactions of apocarotenoids with other lipid-binding proteins, chaperones, and metabolizing enzymes will undoubtedly increase our understanding of the biological roles of these carotenoid metabolites. Vitamin A was recognized as an essential nutrient 100 years ago. In the 1930s, it became clear that dietary β-carotene was cleaved at its central double to yield vitamin A (retinal or β-apo-15′-carotenal). Thus a great deal of research has focused on the central cleavage of provitamin A carotenoids to form vitamin A (retinoids). The mechanisms of formation and the physiological role(s) of noncentral (eccentric) cleavage of both provitamin A carotenoids and nonprovitamin A carotenoids has been less clear. It is becoming apparent that the apocarotenoids exert unique biological activities themselves. These compounds are found in the diet and thus may be absorbed in the intestine, or they may form from enzymatic or nonenzymatic cleavage of the parent carotenoids. The mechanism of action of apocarotenoids in mammals is not fully worked out. However, as detailed in this review, they have profound effects on gene expression and work, at least in part, through the modulation of ligand-activated nuclear receptors. Understanding the interactions of apocarotenoids with other lipid-binding proteins, chaperones, and metabolizing enzymes will undoubtedly increase our understanding of the biological roles of these carotenoid metabolites. Carotenoids are isoprenoids, and over 700 are found in nature (1. 2008; Vol. 4 (Birkhäuser, Basel.)Google Scholar, 2Lu S. Li L. Carotenoid metabolism: biosynthesis, regulation, and beyond.J. Integr. Plant Biol. 2008; 50: 778-785Crossref PubMed Scopus (0) Google Scholar, 3Maresca J.A. Graham J.E. Bryant A.D. 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Chlorophyll also absorbs light in this range, and carotenoids can serve as accessory pigments to enhance light harvesting in photosynthesis. In 1930, Moore demonstrated that orally fed carotene was converted into the colorless form of vitamin A found in the liver of rats (6Moore T. Vitamin A and carotene: the conversion of carotene to vitamin A in vivo.Biochem. J. 1930; 24: 692-702Crossref PubMed Google Scholar). At the same time, the Swiss organic chemist Karrer elucidated the structures of β-carotene and vitamin A (7Karrer P. Helfenstein A. Wehrli H. Wettstein A. Über die konstitution des lycopins und carotins.Helv. Chim. Acta. 1930; 13: 1084-1099Crossref Google Scholar). Carotenoids occur naturally in fruits and vegetables, and they are synthesized in plants and microorganisms. The first C40 carotenoid in the biosynthetic pathway is phytoene. Phytoene is dehydrogenated to other acyclic carotenoids, including lycopene, and ultimately cyclized to carotenes (2Lu S. Li L. Carotenoid metabolism: biosynthesis, regulation, and beyond.J. Integr. Plant Biol. 2008; 50: 778-785Crossref PubMed Scopus (0) Google Scholar). β-Carotene, α-carotene, β-cryptoxanthin, lycopene, and lutein are the primary carotenoids found in human plasma (8Romanchik J.E. Morel D.W. Harrison E.H. Distributions of carotenoids and α-tocopherol among lipoproteins do not change when human plasma is incubated in vitro.J. Nutr. 1995; 125: 2610-2617PubMed Google Scholar). Among them, β-carotene, α-carotene, and β-cryptoxanthin are provitamin A carotenoids, the others are nonprovitamin A carotenoids; lycopene is the acyclic carotenoid and lutein has two hydroxlated rings. To exhibit provitamin A activity, the carotenoid molecule must have at least one unsubstituted β-ionone ring and the correct number and position of methyl groups in the polyene chain (9Wirtz G.M. et al.The substrate specificity of β,β-carotene 15,15’- monooxygenase.Helv. Chim. 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This review focusses on the metabolism of carotenoids, especially β-carotene, in higher vertebrates, including man, with a particular focus on the formation, occurrence, and function of apocarotenoids. The term “apocarotenoid” is a trivial, nonsystematic nomenclature that refers to any cleavage product of a parent 40-carbon carotenoid. Fig. 1 shows all of the possible cleavage products of β-carotene that can arise from oxidative cleavage of the double bonds in the polyene chain. The initial products are aldehydes or ketones. Thus, “β-apo-8′-carotenal” (8′-apo-β-caroten-8′-al) is the longer fragment that arises from cleavage of the 7′, 8′ double bond of β-carotene; the shorter fragment is β-cyclocitral. The naming would be the same for other carotenoids; for example, zeaxanthin, the symmetric xanthophyll that differs from β-carotene by having hydroxyl groups on both β-ionone rings, when cleaved at the 7′, 8′ double bond yields 3-hydroxy-β-apo-8′-carotenal and 3-hydroxycylocitral. Provitamin A carotenoids are partly converted to vitamin A (as retinyl esters) in the intestinal mucosa. In the enterocytes, both carotenoids and retinyl esters are incorporated into chylomicrons and secreted into lymph for delivery to the blood (13Olson J.A. Provitamin A function of carotenoids: the conversion of β-carotene into vitamin A.J. Nutr. 1989; 119: 105-108Crossref PubMed Scopus (280) Google Scholar, 14Parker R.S. Absorption, metabolism, and transport of carotenoids.FASEB J. 1996; 10: 542-551Crossref PubMed Scopus (530) Google Scholar). Following consumption of carotenoid-containing foods, carotenoids are released from their food matrix and incorporated into mixed micelles consisting of lipids and bile components (14Parker R.S. Absorption, metabolism, and transport of carotenoids.FASEB J. 1996; 10: 542-551Crossref PubMed Scopus (530) Google Scholar). 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Retinol then associates with the plasma retinol-binding protein (RBP) in hepatocytes and is secreted from the liver. The retinol-RBP complex (holo RBP) in the blood associates with the thyroxine-binding protein transthyretin (TTR) (34Navab M. Smith J.E. Goodman D.S. Rat plasma prealbumin: metabolic studies on effects of vitamin A status and on tissue distribution.J. Biol. Chem. 1977; 252: 5107-5114Abstract Full Text PDF PubMed Google Scholar, 35O'Byrne S.M. Blaner W.S. Retinol and retinyl esters: biochemistry and physiology.J. Lipid Res. 2013; (54: 1731–1743)Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). It is in this form that retinol is delivered to peripheral sites of action. The metabolism and transport of vitamin A are thoroughly discussed in the accompanying review by O'Byrne and Blaner (35O'Byrne S.M. Blaner W.S. Retinol and retinyl esters: biochemistry and physiology.J. 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A membrane receptor for retinol-binding protein mediates cellular uptake of vitamin A.Science. 2007; 315: 820-825Crossref PubMed Scopus (519) Google Scholar). It is likely that nonreceptor-mediated pathways are also involved in retinol delivery to cells. After delivery to peripheral cells, retinol can be converted to the biologically active hormone atRA. After 1987, with the important discovery of the existence of nuclear retinoic acid receptors (37Giguère V. Ong E.S. Segui P. Evans R.M. Identification of a receptor for the morphogen retinoic acid.Nature. 1987; 330: 624-629Crossref PubMed Google Scholar, 38Petkovich M. Brand N.J. Krust A. Chambon P. A human retinoic acid receptor which belongs to the family of nuclear receptor.Nature. 1987; 330: 444-450Crossref PubMed Google Scholar), researchers started to devote more time to studies related to the mechanisms involved in the regulation of the intracellular concentrations of atRA. 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This reaction results in the formation of β-apo-10′-carotenal and β-ionone (54Kiefer C. Hessel S. Lampert J.M. Vogt K. Lederer M.O. Breithaupt D.E. von Lintig J. Identification and characterization of a mammalian enzyme catalyzing the asymmetric oxidative cleavage of provitamin A.J. Biol. Chem. 2001; 276: 14110-14116Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar) (Fig. 2). Later on, it was found that this enzyme could also catalyze the eccentric cleavage of xanthophylls, such as zeaxanthin and lutein (55Amengual J. Lobo G.P. Golczak M. Li H.N. Klimova T. Hoppel C.L. Wyss A. Palczewski K. von Lintig J. A mitochondrial enzyme degrades carotenoids and protects against oxidative stress.FASEB J. 2011; 25: 948-959Crossref PubMed Scopus (184) Google Scholar, 56Mein J.R. Dolnikowski G.G. Ernst H. Russell R.M. Wang X.D. 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Lobo G.P. Golczak M. Li H.N. Klimova T. Hoppel C.L. Wyss A. Palczewski K. von Lintig J. A mitochondrial enzyme degrades carotenoids and protects against oxidative stress.FASEB J. 2011; 25: 948-959Crossref PubMed Scopus (184) Google Scholar). The mechanism of the central cleavage is still unclear. Originally, the enzyme was thought to be a dioxygenase (46Olson J.A. Hayaishi O. The enzymatic cleavage of beta-carotene into vitamin A by soluble enzymes of rat liver and intestine.Proc. Natl. Acad. Sci. USA. 1965; 54: 1364-1370Crossref PubMed Google Scholar, 47Zeevart J.A.D. Creelman R.A. Metabolism and physiology of abscisic acid.Annu. Rev. Plant Physiol. Plant Mol. Biol. 1988; 39: 439-473Crossref Google Scholar). However, one study presented evidence that it acts as a monooxygenase (58Leuenberger M.G. Engeloch-Jarret C. Woggon W.D. The reaction mechanism of the enzyme-catalyzed central cleavage of β-carotene to retinal.Angew. Chem. Int. Ed. Engl. 2001; 40: 26