HET0016, a potent and selective inhibitor of 20-HETE synthesizing enzyme

被引：168

作者：

Miyata, N ^{[1
]}

Taniguchi, K ^{[1
]}

Seki, T ^{[1
]}

Ishimoto, T ^{[1
]}

Sato-Watanabe, M ^{[1
]}

Yasuda, Y ^{[1
]}

Doi, M ^{[1
]}

Kametani, S ^{[1
]}

Tomishima, Y ^{[1
]}

Ueki, T ^{[1
]}

Sato, M ^{[1
]}

Kameo, K ^{[1
]}

机构：

[1] Taisho Pharmaceut Co Ltd, Med Res Labs, Ohmiya, Saitama 3308530, Japan

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 2001年 / 133卷 / 03期

关键词：

20-HETE; cytochrome P4504A; HET0016; kidney; EETs;

D O I：

10.1038/sj.bjp.0704101

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The present study examined the inhibitory effects of N-Hydroxy-N '-(4-butyl-2-methylphenyl)-formamidine (HET0016) on the renal metabolism of arachidonic acid by cytochrome P450 (CYP) enzymes. HET0016 exhibited a high degree of selectivity in inhibiting the formation of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) in rat renal microsomes. The IC50 value averaged 35 +/-4 nM, whereas the IC50 value for inhibition of the formation of epoxyeicosatrienoic acids by HET0016 averaged 2800 +/- 300 nM. In human renal microsomes, HET0016 potently inhibited the formation of 20-HETE with an IC50 value of 8.9 +/-2.7 nM. Higher concentrations of HET0016 also inhibited the CYP2C9, CYP2D6 and CYP3A4-catalysed substrates oxidation with IC50 values of 3300, 83,900 and 71,000 nM. The IC50 value for HET0016 on cyclo-oxygenase activity was 2300 nM. These results indicate that HET0016 is a potent and selective inhibitor of CYP enzymes responsible for the formation of 20-HETE in man and rat.

引用

页码：325 / 329

页数：5

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