Metabolism and toxicity of styrene in microsomal epoxide hydrolase-deficient mice.
Styrene, which is widely used in manufacturing, is both acutely and chronically toxic to mice. Styrene is metabolized by cytochromes P-450 to the toxic metabolite styrene oxide, which is detoxified via hydrolysis with microsomal epoxide hydrolase (mEH) playing a major role. The purpose of these studies was to characterize the importance of this pathway by determining the hepatotoxicity and pneumotoxicity of styrene in wild-type and mEH-deficient (mEH(-/-)) mice. While the mEH(-/-) mice metabolized styrene to styrene oxide at the same rate as the wild-type mice, as expected there was minimal metabolism of styrene oxide to glycol. mEH(-/-) mice were more susceptible to the lethal effects of styrene. Twenty-four hours following the administration of 200 mg/kg ip styrene, mice demonstrated a greater hepatotoxic response due to styrene, as measured by increased serum sorbitol dehydrogenase activity and greater pneumotoxicity as shown by increased protein levels, cell numbers, and lactate dehydrogenase activity in bronchioalveolar lavage fluid. mEH(-/-) mice were also more susceptible to styrene-induced oxidative stress, as indicated by greater decreases in hepatic glutathione levels 3 h after styrene. Styrene oxide at a dose of 150 mg/kg did not produce hepatotoxicity in either wild-type or mEH(-/-) mice. However, styrene oxide produced pneumotoxicity that was similar in the two strains. Thus, mEH plays an important role in the detoxification of styrene but not for exogenously administered styrene oxide.
School of Health Sciences, Purdue University, West Lafayette, Indiana, USA. gcarlson@purdue.edu
Gary P
GP
Carlson
D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004851:Epoxide Hydrolases / Q000172:deficiency* / Q000378:metabolism; D004852:Epoxy Compounds; D005978:Glutathione / Q000378:metabolism; D007064:L-Iditol 2-Dehydrogenase / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000187:drug effects* / Q000378:metabolism; D020058:Styrene / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity*; D013997:Time Factors
D004852:Epoxy Compounds; D020058:Styrene; C013690:styrene oxide; D007064:L-Iditol 2-Dehydrogenase; D007770:L-Lactate Dehydrogenase; D004851:Epoxide Hydrolases; D005978:Glutathione