Effect of the inhibition of the metabolism of 4-vinylphenol on its hepatotoxicity and pneumotoxicity in rats and mice.
Styrene is known to be both hepatotoxic and pneumotoxic in rodents. 4-Vinylphenol (4-VP) has been shown to be a minor metabolite of styrene in some studies and is a more potent toxicant in mice than either styrene or styrene oxide. 4-VP is metabolized primarily by CYP2E1 and CYP2F2 to an unknown metabolite. The purpose of this study was to use inhibitors of these cytochromes P450 to address the question of whether the parent compound or a metabolite is responsible for 4-VP induced toxicity. Rats as well as mice were found to be susceptible to the toxicity of 4-VP. Prior treatment with either diethyldithiocarbamate or 5-phenyl-1-pentyne as inhibitors of CYP2E1 and CYP2F2 prevented or greatly decreased the hepatotoxicity of 4-VP as assessed by measuring serum sorbitol dehydrogenase and its pneumotoxicity as determined by measurements of cells, protein and lactate dehydrogenase (LDH) activity in bronchoalveolar lavage fluid. Thus the hepatotoxicity and pneumotoxicity of 4-VP are due to a metabolite(s) and not the parent compound.
School of Health Sciences, Purdue University, West Lafayette, IN 47907-1338, USA. gcarlson@purdue.edu
Gary P
GP
Carlson
D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D001555:Benzene Derivatives / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002452:Cell Count; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D004050:Ditiocarb / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009243:NAD / Q000378:metabolism; D010636:Phenols / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013385:Succinate Dehydrogenase / Q000097:blood
D000480:Alkynes; D000931:Antidotes; D001555:Benzene Derivatives; D004791:Enzyme Inhibitors; D010636:Phenols; D009243:NAD; C112922:5-phenyl-1-pentyne; D004050:Ditiocarb; D007770:L-Lactate Dehydrogenase; D013385:Succinate Dehydrogenase; C030626:4-vinylphenol