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A new class of lipid mediators: cytochrome P450 arachidonate metabolites
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  1. Mairead A Carroll,
  2. John C McGiff
  1. Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA
  1. Dr J C McGiff john_mcgiff{at}nymc.edu

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The first reports on the metabolism of arachidonic acid (AA) by cytochrome P450 (CYP) mono-oxygenases appeared in 1981.1 2 The biochemical studies of Capdevila and colleagues have provided the “ground substance” for all future studies. Our initial report in 1984 on the metabolism of AA via CYP pathways by the rabbit medullary thick ascending limb (mTAL) provided evidence that AA metabolism in this segment of the nephron was primarily via the CYP pathway.3 Previously the mTAL was thought to lack the biosynthetic machinery for metabolising AA because of negative immunocytochemical evidence regarding cyclo-oxygenase (COX) capabilities. A subsequent study identified two principal CYP derived AA products generated by the rabbit mTAL, one inhibiting Na+-K+-ATPase and the other relaxing blood vessels.4 Two principal CYP products—20-hydroxyeicosatetraenoic acid (20-HETE) generated by ω/ω-1 hydroxylases and 11,12-epoxyeicosatrienoic acid (11,12-EET) generated by epoxygenases—had been identified in a study of renal zonal CYP derived AA metabolites (fig 1).5 No one then could have anticipated the rise of 20-HETE to its position of pre-eminence among renal eicosanoids, one that functions as a key component in both tubular and vascular mechanisms essential to the regulation of renal haemodynamics and extracellular fluid volume. The first study that pointed to an essential role for 20-HETE in the kidney indicated that it modulated the Na+-K+-2Cl cotransporter in the mTAL, the target for furosemide (frusemide) and the other “high ceiling” diuretics.6 Our companion study had identified 20-HETE as the principal product of AA metabolism in mTAL.7

Figure 1

Arachidonic acid (AA) metabolism by cytochrome P450 dependent mono-oxygenases to ω- and ω-1-hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (epoxides, EETs), and dihydroxyeicosatrienoic acids (diols, DHTs). 20-HETE and 5,6-EET can be converted by cyclo-oxygenase to analogues of prostaglandins.

20-HETE is the pre-eminent renal eicosanoid. …

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