title: Astaxanthin can alter CYP1A-dependent activities via two different mechanisms: induction of protein expression and inhibition of NADPH P450 reductase dependent electron transfer.
abstract: Astaxanthin (Ax), a xanthophyll carotenoid, is reported to induce cytochrome P450 (CYP) 1A-dependent activity. CYP1A is one of the most important enzymes participating in phase I metabolism for chemicals, and it can activate various mutagens. To investigate the effect of Ax on the metabolic activation of a typical promutagen, benzo[a]pyrene by CYP1A, we orally administrated Ax-containing oil (100 mg Ax/kg body weight/day for 3 days) to male Wistar rats. In the treated rat liver, expression of CYP1A1 mRNA, protein, and its activity were significantly increased (5.5-, 8.5-, and 2.5-fold, respectively). In contrast, the activities of phase II enzymes (glutathione S-transferase and glucuronosyl-transferase) were not modulated by Ax-containing oil. As a consequence, the mutagenicity of benzo[a]pyrene was more enhanced in Ax-treated rats, compared with controls in the Ames assay. On the other hand, NADPH P450 reductase activity was decreased in liver microsomes from the treated group. This result suggests the possibility that Ax inhibits the electron supply necessary for CYP catalytic activities and decreases CYP1A activity indirectly. In conclusion, Ax-containing oil intake can alter CYP1A-dependent activities through two different mechanisms: (1) induction of CYP1A1 mRNA, protein expression, and activity; and (2) inhibition of the electron supply for the enzyme.
authors.affiliation: Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9, Kita-ku, Sapporo 060-0818, Japan.
authors.forename: Marumi
authors.initials: M
authors.lastname: Ohno
authors.forename: Wageh S
authors.initials: WS
authors.lastname: Darwish
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ikenaka
authors.forename: Wataru
authors.initials: W
authors.lastname: Miki
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ishizuka
mesh_terms: D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology*; D001564:Benzo(a)pyrene / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D004579:Electron Transport / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009153:Mutagens / Q000633:toxicity; D009251:NADPH-Ferrihemoprotein Reductase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D024341:Xanthophylls / Q000494:pharmacology
chemical_list: D016587:Antimutagenic Agents; D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D009153:Mutagens; D012333:RNA, Messenger; D024341:Xanthophylls; D001564:Benzo(a)pyrene; C005948:astaxanthine; D019363:Cytochrome P-450 CYP1A1; D009251:NADPH-Ferrihemoprotein Reductase; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase