Drug Metabolism and Pharmacokinetics
Online ISSN : 1880-0920
Print ISSN : 1347-4367
ISSN-L : 1347-4367
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Contribution of CYP4A8 to the Formation of 20-Hydroxyeicosatetraenoic Acid from Arachidonic Acid in Rat Kidney
Yoshitaka YAMAGUCHIShirou KIRITAHiroshi HASEGAWAJunko AOYAMASusumu IMAOKASachiko MINAMIYAMAYoshihiko FUNAETakahiko BABATakashi MATSUBARA
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2002 Volume 17 Issue 2 Pages 109-116

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Abstract

  20-Hydroxyeicosatetraenoic acid (20-HETE) has been shown to be an arachidonic acid metabolite of the cytochrome P450 (CYP) enzymes belonging to the CYP4A subfamily and is a predominant regulator of renal vascular tone and tubular ion reabsorption in rat kidney. CYP4A8 is one of the CYP4A enzymes expressed in rat kidney, but its contribution to 20-HETE formation has not been assessed. In order to clarify that the role of CYP4A8, we have developed bacterial expression systems for the expression of recombinant CYP4A8 (rCYP4A8). We also produced an antibody against rCYP4A8 which was used for immunoinhibition and immunohistochemical studies. In a reconstituted system, rCYP4A8 sufficiently catalyzed 20-HETE formation as well as prostaglandin A1 ω-hydroxylation, a marker activity for CYP4A8. In addition, anti-rCYP4A8 sera significantly inhibited prostaglandin A1 ω-hydroxylation and strongly inhibited arachidonic acid ω-hydroxylation in rat kidney microsomes. These observations suggested for the first time that CYP4A8 also contributed to 20-HETE formation in rat kidney. Furthermore, immunohistochemstry suggested that CYP4A8 is present in preglomerular arteries, where 20-HETE has been established to be a vasoconstrictor.

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© 2002 by The Japanese Society for the Study of Xenobiotics
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