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1 Department of Pharmacology, New York Medical College, Valhalla, New York 10595; and 2 Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75235
20-Hydroxyeicosatetraenoic acid (HETE), the cytochrome
P-450 (CYP) 4A 
-hydroxylation
product of arachidonic acid, has potent biological effects on renal
tubular and vascular functions and on the control of arterial pressure.
We have expressed high levels of the rat CYP4A1, -4A2, -4A3, and -4A8
cDNAs, using baculovirus and Sf 9 insect cells. Arachidonic acid
- and -1-hydroxylations were catalyzed by three of
the CYP4A isoforms; the highest catalytic efficiency of 947 nM
1 · min1
for CYP4A1 was followed by 72 and 22 nM1 · min1
for CYP4A2 and CYP4A3, respectively. CYP4A2 and CYP4A3
exhibited an additional arachidonate 11,12-epoxidation activity,
whereas CYP4A1 operated solely as an -hydroxylase. CYP4A8 did not
catalyze arachidonic or linoleic acid but did have a detectable lauric acid -hydroxylation activity. The inhibitory activity of various acetylenic and olefinic fatty acid analogs revealed differences and
indicated isoform-specific inhibition. These studies suggest that
CYP4A1, despite its low expression in extrahepatic tissues, may
constitute the major source of 20-HETE synthesis. Moreover, the ability
of CYP4A2 and -4A3 to catalyze the formation of two opposing
biologically active metabolites, 20-HETE and 11,12-epoxyeicosatrienoic acid, may be of great significance to the regulation of vascular tone.
fatty acid -hydroxylation; 20-hydroxyeicosatetraenoic acid; 11,12-epoxyeicosatrienoic acid
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