Clotrimazole, but not dexamethasone, is a potent in vitro inhibitor of cytochrome P450 isoforms CYP1A and CYP3A in rainbow trout

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• 作者：Viktoriia Burkina ; Vladimir Zlabek ; Galia Zamaratskaia
• 关键词：BFC ; 7-benzyloxy-4-trifluoromethylcoumarin ; BFCOD ; 7-benzyloxy-4-trifluoromethylcoumarin O-debenzylase ; BQ ; 7-benzyloxyquinoline ; BzRes ; benzyloxyresorufin ; CLO ; clotrimazole ; DBF ; dibenzylfluorescein ; DEX ; dexamethasone ; EROD ; ethoxyresorufin O-deethylas
• 刊名：Chemosphere
• 出版年：2013
• 出版时间：August, 2013
• 年：2013
• 卷：92
• 期：9
• 页码：1099-1104
• 全文大小：750 K

文摘

The effects of clotrimazole (CLO) and dexamethasone (DEX), both detected in the aquatic environment, were assessed on inhibition of cytochrome P450 (CYP450) in hepatic microsomes of rainbow trout. Activity of three CYP450 isoforms: ethoxyresorufin O-deethylase (EROD; CYP1A), 7-benzyloxy-4-trifluoromethylcoumarin O-debenzylase (BFCOD; CYP3A) and p-nitrophenol hydroxylase (PNPH; CYP2E1-like protein) was investigated in the presence of four concentrations of CLO and DEX. Clotrimazole in a concentration range of 1-100 ¦ÌM decreased the activity of EROD and BFCOD. The inhibition was reversible, as pre-incubation of the microsomes with CLO, before addition of the substrate, had no effect. EROD activity was non-competitively inhibited with a K_i of 0.5 ¦ÌM, and BFCOD activity revealed competitive inhibition with a K_i of 0.04 ¦ÌM. The relatively low K_i for CLO inhibition of EROD and BFCOD activity may indicate that the ability of CYP1A and CYP3A to metabolize xenobiotics is reduced in the presence of CLO. PNPH activity was not affected by CLO. DEX showed no inhibitory potency on any investigated reaction. CLO, but not DEX, inhibited EROD and BFCOD activity by different mechanisms.