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标题：Cytochrome P450 4A Isoform Inhibitory Profile of N-Hydroxy-N′-(4-butyl-2-methylphenyl)-formamidine (HET0016), a Selective Inhibitor of 20-HETE Synthesis
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作者：Takayuki Seki ; Mong-Heng Wang ; Noriyuki Miyata 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2005
卷号：28
期号：9
页码：1651-1654
DOI：10.1248/bpb.28.1651
出版社：The Pharmaceutical Society of Japan
摘要：We examined the effect of N -hydroxy- N ′-(4-butyl-2-methylphenyl)-formamidine) (HET0016), an inhibitor of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) synthesis on the ω-hydroxylation and epoxidation of arachidonic acid (AA) catalyzed by recombinant cytochrome P450 4A1 (CYP4A1), CYP4A2 and CYP4A3, and characterized the enzyme inhibitory profile of HET0016. The IC₅₀ values of HET0016 for recombinant CYP4A1-, CYP4A2- and CYP4A3-catalyzed 20-HETE synthesis averaged 17.7 n M , 12.1 n M and 20.6 n M , respectively. The IC₅₀ value for production of 11,12-epoxy-5,8,14-eicosatrienoic acid (11,12-EET) by CYP4A2 and 4A3 averaged 12.7 n M and 22.0 n M , respectively. The IC₅₀ value for CYP2C11 activity was 611 n M which was much greater than that for CYP4As. The initial velocity study showed the K _i value of HET0016 for CYP4A1 was 19.5 n M and a plot of V _max versus amount of recombinant CYP4A1 added shows HET0016 is an irreversible non-competitive inhibitor. These results indicate that HET0016 is a selective, non-competitive and irreversible inhibitor of CYP4A.
关键词：cytochrome P450 A4;20-hydroxy-5,8,11,14-eicosatetraenoic acid;HET0016;kinetics