Stereoselectivity of styrene oxidation in microsomes and in purified cytochrome P-450 enzymes from rat liver.
The stereochemistry of the cytochrome P-450(P-450)-dependent oxidation of styrene to styrene 7,8-oxide (SO) enantiomers was evaluated with rat hepatic microsomes and with individual rat liver P-450 enzymes in reconstituted monooxygenase systems. The stereoselectivity of the monooxygenase reaction with styrene was determined by high-performance liquid chromatographic analysis of the glutathione conjugates formed quantitatively from SO, the product of the monooxygenase reaction. Hepatic microsomes from control rats oxidized styrene at a rate of 13.1 +/- 4.5 nmol/min/nmol of P-450 and with a ratio of the amount of the (R)-styrene 7,8-oxide enantiomer to the amount of the (S)-styrene 7,8-oxide enantiomer (R/S) SO ratio of 0.65 +/- 0.1. These values were determined under incubation conditions in which epoxide hydrolase activity was inhibited by cyclohexene oxide, and at least 95% of the SO formed was converted enzymatically to glutathione conjugates. Treatment of rats i.p. with phenobarbital (PB) or beta-naphthoflavone (beta NF) caused changes in both parameters. Whereas the rates of oxidation in hepatic microsomes prepared from PB-treated rats was unchanged at 15.4 +/- 7.5 nmol/min/nmol of P-450 and decreased in hepatic microsomes from beta NF-treated rats to 9.4 +/- 2.8 nmol/min/nmol of P-450, the preference for formation of the R-enantiomer increased as the R/S ratio changed to 0.92 +/- 0.1 for PB and 1.25 +/- 0.1 for beta NF.(ABSTRACT TRUNCATED AT 250 WORDS)
Foureman
G L
GL
Laboratory of Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
Harris
C
C
Guengerich
F P
FP
Bend
J R
JR
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D020058:Styrene; D013343:Styrenes / Q000378:metabolism*; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D013343:Styrenes; D020058:Styrene; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; D010634:Phenobarbital