Cytochrome P450 4A Isoform Inhibitory Profile of N-Hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016), a Selective Inhibitor of 20-HETE Synthesis(Pharmacology)

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概要

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• 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 IC_<50> values of HET0016 for recombinant CYP4A1-, CYP4A2- and CYP4A3-catalyzed 20-HETE synthesis averaged 17.7nM, 12.1nM and 20.6nM, respectively. The IC_<50> value for production of 11,12-epoxy-5,8,14-eicosatrienoic acid (11,12-EET) by CYP4A2 and 4A3 averaged 12.7nM and 22.0nM, respectively. The IC_<50> value for CYP2C11 activity was 611nM which was much greater than that for CYP4As. The initial velocity study showed the K_i value of HET0016 for CYP4A1 was 19.5nM 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.

• 公益社団法人日本薬学会の論文
• 2005-09-01

著者

• SEKI Takayuki

  Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd.

• MIYATA Noriyuki

  Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd.

• Seki Takayuki

  Medicinal Pharmacology Laboratory Medicinal Research Laboratories Taisho Pharmaceutical Co. Ltd.

• Laniado Schwartzman

  Department Of Pharmacology New York Medical College

• WANG Mong

  Department of Physiology, Medical College of Georgia

• Miyata Noriyuki

  Medicinal Pharmacology Laboratory Medicinal Research Laboratories Taisho Pharmaceutical Co. Ltd.

• Wang Mong

  Department Of Physiology Medical College Of Georgia

• Wang Mong-Heng

  Department of Physiology, Medical College of Georgia

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• Role of 20-hydroxyeicosatetraenoic acid (20-HETE) in vascular system
• Cytochrome P450 4A Isoform Inhibitory Profile of N-Hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016), a Selective Inhibitor of 20-HETE Synthesis(Pharmacology)
• Suppression of AGE Precursor Formation Following Unilateral Ureteral Obstruction in Mouse Kidneys by Transgenic Expression of α-Dicarbonyl/L-Xylulose Reductase

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