Molecular requirements for inhibition of cytochrome P450 activities by roquefortine

被引:37
作者
Aninat, C
Hayashi, Y
André, F
Delaforge, M
机构
[1] CEA Saclay, Lab Etud Metab Medicaments, Serv Pharmacol & Immunol, F-91191 Gif Sur Yvette, France
[2] Kyoto Pharmaceut Univ, Ctr Frontier Res Med Sci, Yamashina Ku, Kyoto 6078412, Japan
[3] CEA Saclay, CNRS URA 2096, Dept Biol Cellulaire & Mol, F-91191 Gif Sur Yvette, France
关键词
D O I
10.1021/tx015512l
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Roquefortine, a cyclopeptide derived from the diketopiperazine cyclo(Trp-dehydroHis), is a secondary metabolite produced by several Penicillium species. It has been reported to cause neurotoxic effect and to inhibit Gram-positive bacteria growth. The mechanisms responsible for its toxicity and metabolism are still unknown. In this study, we investigated the interaction of roquefortine with mammalian cytochromes P450. Roquefortine interaction with rat and human liver cytochromes P450 was monitored by difference UV-vis spectroscopy. It was found to interact with different forms of the cytochromes, giving rise to a type II difference spectrum, characteristic of the binding of an amino function to the heme iron. Roquefortine exhibited high affinity for microsomes from rats treated with various inducers, the K-s values being in the range 0.2-8 muM. Similar results were observed with human P450 enzymes 1A1, 1A2, 2D6, and 3A4. Roquefortine had no effect on NAPDH cytochrome c reductase. Therefore, inhibition of NADPH consumption was observed using various rat liver microsomes alone or in the presence of 100 muM testosterone in the case of dexamethasone (DEX)-rat microsomes. Enzymatic inhibition was studied in terms of P450 3A activities, i.e., testosterone 6 beta -hydroxylase (IC50 around 10 muM) or bromocriptine metabolism (IC50 > 50 muM) using DEX-rat liver microsomes or P450 3A4, benzphetamine N-demethylase using phenobarbital-rat liver microsomes (IC50 > 30 muM), and ethoxyresorufin metabolism using 3-methyleholanthrene-rat liver microsomes (IC50 0.1 muM), P450 1A1, and 1A2. Roquefortine was compared with compounds of similar structure: cyclo(Phe-His), cyclo(Phe-dehydroHis), cyclo(Trp-His), phenylahistin. These studies indicate that the =N- imidazole moiety coordinates with the heme iron, and suggest that the dehydroHis moiety and the presence of a fused tetracycle play an important part in roquefortine inhibitory power.
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页码:1259 / 1265
页数:7
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