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Vol. 285, Issue 3, 1327-1336, June 1998
Department of Biochemistry, Mount Sinai School of Medicine, New
York, New York
20-Hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) is a principal
arachidonic acid (AA) metabolite formed via
P450-dependent oxidation in hepatic and renal microsomes. Although
20-HETE plays an important role in the regulation of cell and/or organ
physiology, the P450 enzyme(s) catalyzing its formation in humans
remain undefined. In this study, we have characterized AA
-hydroxylation to 20-HETE by human hepatic microsomes and identified
the underlying P450s. Analysis of microsomal AA -hydroxylation
revealed biphasic kinetics (KM1 and
VMAX1 = 23 µM and 5.5 min
1; KM2 and
VMAX2 = 144 µM and 18.8 min1) consistent with catalysis by at least
two enzymes. Of the human P450s examined, CYP4A11 and CYP4F2 were both
potent AA -hydroxylases, exhibiting rates of 15.6 and 6.8 nmol
20-HETE formed/min/nmol P450, respectively. Kinetic parameters of
20-HETE formation by CYP4F2 (KM = 24 µM;
VMAX = 7.4 min1)
and CYP4A11 (KM = 228 µM;
VMAX = 49.1 min1)
resembled the low and high KM components,
respectively, found in liver microsomes. Antibodies to CYP4F2 markedly
inhibited (93.4 ± 6%; n = 5) formation of
20-HETE by hepatic microsomes, whereas antibodies to CYP4A11 were much
less inhibitory (13.0 ± 9%; n = 5).
Moreover, a strong correlation (r = 0.78; P < .02) was found between microsomal CYP4F2 content and AA
-hydroxylation among nine subjects. The correlation
(r = 0.76; P < .02) also noted between
CYP4A11 content and 20-HETE formation stemmed from the relationship
(r = 0.83; P < .02) between hepatic CYP4A11
and CYP4F2 levels in the subjects. Finally, immunoblot analysis
revealed that in addition to liver, both P450s also were expressed in
human kidney. Our results indicate that AA -hydroxylation in human liver is catalyzed by two enzymes of the CYP4 gene family, namely CYP4F2 and CYP4A11, and that CYP4F2 underlies most 20-HETE formation occurring at relevant AA concentrations.
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