Effects of the antifungal imidazole ketoconazole on CYPIA and CYP3A in rainbow trout and killifish
Effects of the antifungal imidazole ketoconazole on CYPIA and CYP3A in rainbow trout and killifish
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DOI：
10.1897/03-155
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发表时间：
2004-05-01
影响因子：
4.1
通讯作者：
Celander, MC
中科院分区：
文献类型：
--
作者：
Hegelund, T;Ottosson, K;Celander, MC
N-取代咪唑的使用很广泛，在水生环境中检测到咪唑和三唑类杀真菌剂，并显示其在鱼类中具有生物累积性。我们研究了模型咪唑，酮康唑，对药物代谢细胞色素P450（CYP 19）形式的影响。我们专注于细胞色素P4501 A（CYP 1A）和细胞色素P4503 A（CYP 3A）的表达和活动在青少年虹鳟鱼和成年？在虹鳟鱼中诱导了CYP 1A的表达（mRNA，蛋白质）和活性，而在鳉鱼中没有观察到酮康唑对CYP 1A蛋白表达的影响。在虹鳟鱼体内和体外实验中，酮康唑暴露与肝脏CYP 1A介导的乙氧基试卤灵O-脱乙基酶（EROD）活性之间存在双相剂量反应关系，这意味着较高剂量的酮康唑抑制CYP 1A活性。在体内暴露于酮康唑的虹鳟鱼中观察到CYP 3A蛋白水平的轻微诱导。然而，CYP 3A介导的苄氧基-4-[三氟甲基]-香豆素（BFC）O-脱苄氧基酶活性降低虹鳟鱼和鳉鱼与酮康唑治疗。体外抑制研究证实，酮康唑是这些种属中CYP 3A和CYP 1A酶活性的强效抑制剂。本研究表明，酮康唑诱导虹鳟鱼CYP 1A和CYP 3A的表达。然而，酮康唑最显著的作用是虹鳟鱼和鳉鱼中CYP 3A催化活性降低60 - 90%。
The use of N-substituted imidazoles is widespread, and imidazole and triazole fungicides have been detected in the aquatic environment and shown to bioaccumulate in fish. We have investigated effects of the model imidazole, ketoconazole, on drug-metabolizing cytochrome P450 (CYP) forms. We focused on cytochrome P4501A (CYP1A) and cytochrome P4503A (CYP3A) expression and activities in juvenile rainbow trout and in adult killifish. The CYP1A expression (mRNA, protein) and activity was induced in rainbow trout, whereas in killifish no effect of ketoconazole on CYP1A protein expression was observed. A biphasic dose-response relationship was observed between ketoconazole exposure and hepatic CYP1A-mediated ethoxyresorufin O-deethylase (EROD) activity in rainbow trout in vitro and in vivo, implying that higher doses of ketoconazole inhibit CYP1A activities. Slight induction of CYP3A protein levels was observed in rainbow trout exposed in vivo to ketoconazole. However, the CYP3A-mediated benzyloxy-4-[trifluoromethyl]-coumarin (BFC) O-debenzyloxylase activity was reduced in rainbow trout and killifish treated with ketoconazole. In vitro inhibition studies confirmed that ketoconazole was a potent inhibitor of both CYP3A and CYP1A enzyme activities in these species. This Study showed that ketoconazole induced CYP1A and CYP3A expression in rainbow trout. However, the most pronounced effect of ketoconazole was a 60 to 90% decrease in CYP3A catalytic activities in rainbow trout and in killifish.