Metabolism and toxicity of the styrene metabolite 4-vinylphenol in CYP2E1 knockout mice.
4-vinylphenol (4-VP) is a minor metabolite of styrene and is several times more potent as a hepatotoxicant and pneumotoxicant than is either the parent compound or the major metabolite of styrene, styrene oxide. 4-VP is metabolized primarily by CYP2E1 and CYP2F2. To further elucidate the possible role of 4-VP in styrene-induced toxicity and the importance of its metabolism by CYP2E1, the metabolism of 4-VP and its hepatotoxicity and pneumotoxicity were compared in wild-type and CYP2E1 knockout mice. There were no marked differences between the wild-type and knockout mice in the rates of microsomal metabolism of 4-VP in either liver or lung. This unexpected result mimics previous findings with styrene metabolism in wild-type and knockout mice. When mice were administered 100 mg/kg 4-VP ip, the knockout mice were more susceptible to hepatotoxicity, as measured by increases in serum sorbitol dehydrogenase activity, than were the wild-type mice. There was no significant difference in the pneumotoxicity between the two strains. The data suggest that, as for styrene, additional cytochromes P-450 are involved in the metabolism of 4-VP.
Vogie
Kelly
K
School of Health Sciences, Purdue University, West Lafayette, Indiana 47907-2051, USA.
Mantick
Nancy
N
Carlson
Gary
G
D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010636:Phenols / Q000378:metabolism* / Q000633:toxicity*
D010636:Phenols; D019392:Cytochrome P-450 CYP2E1; C030626:4-vinylphenol