Comparison of the susceptibility of wild-type and CYP2E1 knockout mice to the hepatotoxic and pneumotoxic effects of styrene and styrene oxide.
Styrene causes both liver and lung damage in non-Swiss albino, CD-1, and other strains of mice. This is considered to be due to the bioactivation of styrene to styrene oxide by cytochromes P450, principally CYP2E1 and CYP2F2. If so, one would expect CYP2E1 knockout mice to be less susceptible to styrene-induced toxicity than wild-type mice. However, previous in vitro and in vivo studies demonstrated little difference in the metabolism of styrene to styrene oxide between wild-type and CYP2E1 knockout mice. These findings would suggest that there should be no difference in the toxic responses to styrene between these two strains. To determine which of these possibilities was correct, styrene (600 mg/kg) or styrene oxide (300 mg/kg) was administered i.p. 24 h prior to measurement of serum sorbitol dehydrogenase as a biomarker of hepatotoxicity or lactate dehydrogenase activity, protein, and cells in bronchoalveolar lavage fluid as biomarkers for pneumotoxicity. Styrene was more hepatotoxic in the wild-type mice than in the knockout mice suggesting CYP2E1 activity is important. Strain differences were not observed with styrene oxide indicating no difference in intrinsic susceptibility. For lung, the response was similar in both strains to both styrene and styrene oxide supporting the idea that CYP2F2 is important in the bioactivation of styrene in this tissue and that there is no strain difference in susceptibility to the active metabolite.
Carlson
Gary P
GP
School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, IN 47907-2051, USA. gcarlson@purdue.edu
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007064:L-Iditol 2-Dehydrogenase / Q000032:analysis; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D020058:Styrene / Q000378:metabolism / Q000633:toxicity*
D015415:Biomarkers; D004852:Epoxy Compounds; D020058:Styrene; C013690:styrene oxide; D007064:L-Iditol 2-Dehydrogenase; D019392:Cytochrome P-450 CYP2E1