Effects of inducers and inhibitors on the microsomal metabolism of styrene to styrene oxide in mice.
Styrene is both hepatotoxic and pneumotoxic in mice, with non-Swiss albino (NSA) mice being more sensitive than Swiss (CD-1) mice. The toxicity of styrene is potentiated by treatment with phenobarbital, beta-naphthoflavone, or pyridine. Since the toxicity of styrene is generally associated with its metabolism to styrene oxide (SO), the formation of SO by hepatic and pulmonary microsomes of NSA and CD-1 mice was measured to examine correlations with toxicity. Both enantiomers of SO were quantified since the R-SO enantiomer is more toxic than the S-SO enantiomer. No strain differences in rates of styrene metabolism or enantiomeric ratio were observed in control mice or mice treated with inducers. Pyridine, an inducer of CYP2E1, increased S-SO but not R-SO formation in liver. Phenobarbital, an inducer of CYP2B, increased the production of both enantiomers. beta-Naphthoflavone, an inducer of CYP1A, had no effect. None of the inducers had any effect in lung. Addition of the CYP2E1 inhibitor diethyldithiocarbamate decreased the formation of both enantiomers in both tissues from control mice, whereas 5-phenyl-1-pentyne (an inhibitor of CYP2F2) inhibited metabolism primarily in lung. In both control and phenobarbital-treated mice, SKF525A inhibited both R-SO and S-SO in liver but only S-SO in lung. Thus there are tissue differences in metabolism and susceptibility to induction and inhibition but no strain differences in metabolism to explain differences in susceptibility to styrene-induced toxicity.
Carlson
G P
GP
School of Health Sciences, Purdue University, West Lafayette, Indiana 47907-1338, USA.
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004050:Ditiocarb / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013045:Species Specificity; D020058:Styrene; D013343:Styrenes / Q000378:metabolism*; D019324:beta-Naphthoflavone / Q000494:pharmacology
D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D011725:Pyridines; D013343:Styrenes; D020058:Styrene; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; C013690:styrene oxide; C023666:pyridine; D010634:Phenobarbital