Cytochrome P-450 enzyme-specific control of the regio- and enantiofacial selectivity of the microsomal arachidonic acid epoxygenase.
Chiral analysis of the rat liver microsomal arachidonic acid epoxygenase metabolites shows enantioselective formation of 8,9-, 11,12-, and 14,15-cis-epoxyeicosatrienoic acids in an approximately 2:1, 4:1, and 2:1 ratio of antipodes, respectively. Animal treatment with the cytochrome P-450 inducer phenobarbital increased the overall enantiofacial selectivity of the microsomal epoxygenase and caused a concomitant inversion in the absolute configurations of its metabolites. These effects of phenobarbital were time-dependent and temporally linked to increases in the concentration of microsomal cytochrome P-450 enzymes. Reconstitution of the epoxygenase reaction utilizing several purified cytochrome P-450 demonstrated that the asymmetry of epoxidation is under cytochrome P-450 enzyme control. These results established that the chirality of the hepatic arachidonic acid epoxygenase is under regulatory control and confirm cytochromes P-450 IIB1 and IIB2 as two of the endogenous epoxygenases induced in vivo by phenobarbital.
Capdevila
J H
JH
Department of Medicine (Nephrology Division), Vanderbilt University Medical School, Nashville, Tennessee 37232.
Karara
A
A
Waxman
D J
DJ
Martin
M V
MV
Falck
J R
JR
Guenguerich
F P
FP
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010105:Oxygenases / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013379:Substrate Specificity; D019324:beta-Naphthoflavone
D001571:Benzoflavones; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D019324:beta-Naphthoflavone; C050715:8,9-epoxyeicosatrienoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D000090762:Cytochrome P-450 CYP2J2; D015126:8,11,14-Eicosatrienoic Acid; D010634:Phenobarbital