beta-Cryptoxanthin, a novel natural RAR ligand, induces ATP-binding cassette transporters in macrophages.
Despite its serious adverse effects, recent accumulating evidence suggests that a physiological retinoic acid receptor (RAR) agonist, all-trans retinoic acid (atRA), exhibits preventive effects on atherogenesis. Therefore, the present study was designed to explore novel natural RAR ligands with anti-atherogenic effects in order to identify and develop a drug without severe side effects. Among xanthophylls and carotenoids studied, beta-cryptoxanthin and lutein exhibited RAR ligand activity in yeast two-hybrid system that was found to be completely abolished by the RAR pan-antagonist LE540. Furthermore, these molecules can bind the RAR ligand-binding domain in the CoA-BAP system but not RXR ligand-binding domain. These results indicate that both beta-cryptoxanthin and lutein serve as ligands for RAR, but not RXR, although their binding affinity was three orders of magnitude lower than that of atRA. Additionally, when applied to macrophages, beta-cryptoxanthin indeed was found to induce the ATP-binding cassette transporter A1 (ABCA1) and ABCG1 mRNAs, which exert anti-atherosclerotic effects by preventing cholesteryl ester accumulation in macrophages. The induction of ABCA1 proteins by beta-cryptoxanthin as well as atRA was abrogated by LE540. In summary, beta-cryptoxanthin appears to be more an efficient provitamin A source than other carotenoids and xanthophylls including beta-carotene, since beta-cryptoxanthin can act not only as a RAR agonist but also a source of vitamin A. Taking into account that the pharmacodynamics difference between beta-cryptoxanthin and atRA, beta-cryptoxanthin appears to exert beneficial effects on atherogenesis through RAR activation in the manner different from atRA.
Matsumoto
Akira
A
Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan.
Mizukami
Hajime
H
Mizuno
Satoshi
S
Umegaki
Keizo
K
Nishikawa
Jun-ichi
J
Shudo
Koichi
K
Kagechika
Hiroyuki
H
Inoue
Makoto
M
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D065366:Cryptoxanthins; D003984:Dibenzazepines / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D008074:Lipoproteins / Q000235:genetics*; D014975:Lutein / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D020798:Two-Hybrid System Techniques; D024341:Xanthophylls / Q000494:pharmacology*
C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D065366:Cryptoxanthins; D003984:Dibenzazepines; C104183:LE 540; D008074:Lipoproteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D024341:Xanthophylls; D014975:Lutein