Miyata N, Taniguchi K, Seki T, Ishimoto T, Sato-Watanabe M, Yasuda Y, Doi M, Kametani S, Tomishima Y, Ueki T, Sato M, Kameo K
Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Yoshino-cho, Ohmiya, Saitama 330-8530, Japan.
Br J Pharmacol. 2001 Jun;133(3):325-9. doi: 10.1038/sj.bjp.0704101.
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 IC(50) value averaged 35+/-4 nM, whereas the IC(50) 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 IC(50) value of 8.9+/-2.7 nM. Higher concentrations of HET0016 also inhibited the CYP2C9, CYP2D6 and CYP3A4-catalysed substrates oxidation with IC(50) values of 3300, 83,900 and 71,000 nM. The IC(50) 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.
本研究检测了N-羟基-N'-(4-丁基-2-甲基苯基)甲脒（HET0016）对细胞色素P450（CYP）酶介导的花生四烯酸肾代谢的抑制作用。HET0016在抑制大鼠肾微粒体中20-羟基-5,8,11,14-二十碳四烯酸（20-HETE）形成方面表现出高度选择性。其半数抑制浓度（IC50）值平均为35±4 nM，而HET0016抑制环氧二十碳三烯酸形成的IC50值平均为2800±300 nM。在人肾微粒体中，HET0016能有效抑制20-HETE的形成，IC50值为8.9±2.7 nM。更高浓度的HET0016还能抑制CYP2C9、CYP2D6和CYP3A4催化的底物氧化，IC50值分别为3300、83900和71000 nM。HET0016对环氧化酶活性的IC50值为2300 nM。这些结果表明，HET0016是人和大鼠体内负责20-HETE形成的CYP酶的强效选择性抑制剂。
