title: Naturally occurring eccentric cleavage products of provitamin A β-carotene function as antagonists of retinoic acid receptors.
abstract: β-Carotene is the major dietary source of provitamin A. Central cleavage of β-carotene catalyzed by β-carotene oxygenase 1 yields two molecules of retinaldehyde. Subsequent oxidation produces all-trans-retinoic acid (ATRA), which functions as a ligand for a family of nuclear transcription factors, the retinoic acid receptors (RARs). Eccentric cleavage of β-carotene at non-central double bonds is catalyzed by other enzymes and can also occur non-enzymatically. The products of these reactions are β-apocarotenals and β-apocarotenones, whose biological functions in mammals are unknown. We used reporter gene assays to show that none of the β-apocarotenoids significantly activated RARs. Importantly, however, β-apo-14'-carotenal, β-apo-14'-carotenoic acid, and β-apo-13-carotenone antagonized ATRA-induced transactivation of RARs. Competitive radioligand binding assays demonstrated that these putative RAR antagonists compete directly with retinoic acid for high affinity binding to purified receptors. Molecular modeling studies confirmed that β-apo-13-carotenone can interact directly with the ligand binding site of the retinoid receptors. β-Apo-13-carotenone and the β-apo-14'-carotenoids inhibited ATRA-induced expression of retinoid responsive genes in Hep G2 cells. Finally, we developed an LC/MS method and found 3-5 nm β-apo-13-carotenone was present in human plasma. These findings suggest that β-apocarotenoids function as naturally occurring retinoid antagonists. The antagonism of retinoid signaling by these metabolites may have implications for the activities of dietary β-carotene as a provitamin A and as a modulator of risk for cardiovascular disease and cancer.
authors.affiliation: Department of Human Nutrition, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Abdulkerim
authors.initials: A
authors.lastname: Eroglu
authors.forename: Damian P
authors.initials: DP
authors.lastname: Hruszkewycz
authors.forename: Carlo
authors.initials: C
authors.lastname: dela Sena
authors.forename: Sureshbabu
authors.initials: S
authors.lastname: Narayanasamy
authors.forename: Ken M
authors.initials: KM
authors.lastname: Riedl
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Kopec
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Schwartz
authors.forename: Robert W
authors.initials: RW
authors.lastname: Curley
authors.forename: Earl H
authors.initials: EH
authors.lastname: Harrison
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D019556:COS Cells; D002338:Carotenoids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D003577:Cytochrome P-450 Enzyme System; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011869:Radioligand Assay; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072516:Retinoic Acid 4-Hydroxylase; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation / Q000187:drug effects; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D014316:Tritium; D019207:beta Carotene / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018168:Receptors, Retinoic Acid; C483690:apo-14'-carotenoic acid; C082925:retinoic acid receptor beta; D019207:beta Carotene; D014316:Tritium; D002338:Carotenoids; D014212:Tretinoin; C071311:beta-apo-14'-carotenal; C071310:beta-apo-13-carotenone; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase