Current Drug Metabolism

Michael Sinz
Bristol Myers Squibb
Wallingford, CT
USA

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Kidney CYP450 Enzymes: Biological Actions Beyond Drug Metabolism

Author(s): X. Zhao, J. D. Imig.

Abstract:

Arachidonic acid can be metabolized by cytochrome P450 (CYP450) enzymes to 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs), their corresponding dihydroxyeicosatrienoic acids (DHETs), and 20-hydroxyeicosatetraenoic acid (20-HETE). These arachidonic acid metabolites are involved in the regulation of renal epithelial transport and vascular function. 20- HETE and EETs are produced in the renal microvascular smooth muscle cells and endothelial cells, respectively. 20-HETE constricts the preglomerular arterioles by inhibiting K+ channels, and contributes importantly to renal blood flow autoregulatory responsiveness of the afferent arterioles. EETs dilate the preglomerular arterioles by activating the renal smooth muscle cell Ca2+-activated K+ channels and hyperpolarizing smooth muscle cells. These EET actions are consistent with their identification as endotheliumderived hyperpolarizing factors (EDHFs). In the kidney, EETs and 20-HETE are also produced in the proximal tubule and the thick ascending loop of Henle, and these metabolites modulate ion transport in the proximal tubules and the thick ascending limb by inhibiting Na+-K+-ATPase and the Na+-K+-2Cl- cotransporter. CYP450 metabolites also act as second messengers for many paracrine and hormonal agents, including endothelin, nitric oxide, and angiotensin II. The production of kidney CYP450 arachidonic acid metabolites is altered in diabetes, pregnancy, hepatorenal syndrome, and in various models of hypertension, and it is likely that changes in this system contribute to the abnormalities in renal function that are associated with many of these conditions.

Keywords: cytochrome p450, cyp 450, cyp450 w-hydroxylase, cyp450 epoxygenase, p450 metabolites

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Article Details

VOLUME: 4
ISSUE: 1
Year: 2003
Page: [73 - 84]
Pages: 12
DOI: 10.2174/1389200033336892