Author: Abdulkerim EroğluPublisher:
ISBN:
Category :
Languages : en
Pages : 129
Book Description
Abstract: Beta-carotene (BC) is the major dietary source of provitamin A. Central cleavage of BC catalyzed by beta-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 BC at non-central double bonds is catalyzed by other enzymes and can also occur non-enzymatically. The products of these reactions are beta-apocarotenals and beta-apocarotenones, whose biological functions in mammals are unknown. We used reporter gene assays to show that none of the beta-apocarotenoids significantly activated RARs and RXR[alpha]. Beta-Apo-13-carotenone was found to antagonize the activation of RXR[alpha] by 9-cis-retinoic acid and was effective at concentrations as low as 1 nM. Molecular modeling studies revealed that beta-apo-13-carotenone makes molecular interactions like an antagonist of RXR[alpha]. The results suggest a possible function of BACs on RXR[alpha] signaling. Moreover, beta-apo-14'-carotenal, beta-apo-14'-carotenoic acid, and beta-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 beta-apo-13-carotenone can directly interact with the ligand binding site of the retinoid receptors. Beta-Apo-13-carotenone and the beta-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 beta-apo-13-carotenone was present in human plasma. These findings suggest that beta-apocarotenoids function as naturally-occurring retinoid antagonists. We have also tested apo-lycopenoids that have a structural resemblance to beta-apo-13-carotenone to see if they exert a similar action as beta-apo-13-carotenone in modulating retinoid receptor activation. We found that apo-13-lycopenone was able to block ATRA induced expression of RAR[beta] and CYP26A1 like the action of beta-apo-13-carotenone. This suggests that the ionone ring may not be prerequisite for beta-apo-13-carotenone's binding to RARs. The antagonism of retinoid signaling by these metabolites may have implications for the activities of dietary beta-carotene as a provitamin A and as a modulator of risk for cardiovascular disease and cancer.
