title: Modification of the metabolism and toxicity of styrene and styrene oxide in hepatic cytochrome P450 reductase deficient mice and CYP2F2 deficient mice.
abstract: Styrene causes toxicity in both the lung and the liver. The study of the relationship of this toxicity to the metabolism of styrene has been aided by the use of knockout mice for both bioactivation and detoxification pathways. It has been hypothesized that CYP2E1 is primarily responsible for styrene bioactivation in mouse liver and CYP2F2 in mouse lung. Two knockout strains were used in the current studies. Mice deficient in hepatic cytochrome P450 reductase had much less hepatic metabolism of styrene to styrene oxide. Styrene (600 mg/kg, i.p.) caused significant hepatotoxicity, as determined by serum sorbitol dehydrogenase and glutathione levels, in the wild-type but not in the knockout mice. It caused lung toxicity, as determined by protein levels, cell number, and lactate dehydrogenase activity in the bronchioalveolar lavage fluid of wild-type mice, but this effect was less in the knockout mice. In CYP2F2 knockout mice there was only a small decrease in the hepatic metabolism of styrene but a very large decrease in pulmonary metabolism. As expected the CYP2F2 knockout and wild-type mice were equally susceptible to styrene-induced hepatotoxicity, but the knockout mice were less susceptible to styrene-induced pneumotoxicity. Although the results are inconsistent with the simple hypothesis that styrene pneumotoxicity is due to the bioactivation of styrene to styrene oxide by CYYP2F2, they demonstrate the importance of both liver and lung in the metabolism of styrene, but additional pharmacokinetic studies are needed to help clarify the relationship between target organ metabolism and susceptibility.
authors.affiliation: School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA. gcarlson@purdue.edu
authors.forename: Gary P
authors.initials: GP
authors.lastname: Carlson
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004852:Epoxy Compounds / Q000378:metabolism / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D020058:Styrene / Q000378:metabolism / Q000633:toxicity*
chemical_list: D004852:Epoxy Compounds; D020058:Styrene; D003577:Cytochrome P-450 Enzyme System; C013690:styrene oxide; D007064:L-Iditol 2-Dehydrogenase; C110333:Cyp2f2 protein, mouse; D009251:NADPH-Ferrihemoprotein Reductase; D005978:Glutathione