Role of CYP2E1 in Hepatocarcinogenesis and Hepatotoxicity

다국어 초록 (Multilingual Abstract)

CYP2E1 metabolize many low-molecular-weight toxins and carcinogens, such as N-nitrosamines, benzene, acetaminophen and carbon tetrachloride. Roles of CYP2E1 in diethylnitrosoamine (DEN)-mediated carcinogenesis and in thioacetamide (TAA)-induced hepatotoxicity are not fully understood in vivo. To clarify this, we carried out DEN-induced hepatocarcinogenesis and TAA-induced hepatotoxicity test using CYP2E1-null mice. For liver carcinogenesis, male wild-type and CYP2E1-null mice were treated with DEN at 14-day of age, and were sacrificed at weeks 24 and 36 for investigation of tumors and at 6 h, days 1 and 2 for examination of apoptosis and its relating genes after DEN treatment. Liver weight of wild-type mice significantly different compared to that of CYP2E1-null mice at weeks 24 and 36 (p<0.01). Liver tumor incidence of CYP2E1-null mice significantly decreased compared to that of wild-type mice (p<0.01), and tumor multiplicities were also significantly decreased compared to wild mice at weeks 24 and 36 (p<0.05, p<0.01, respectively). In short-term study, apoptotic index, caspase-3 mRNA and Bax mRNA of CYP2E1-null mice were significantly different compared to those of wild-type mice (p<0.05). For liver toxicity, male wild-type and CYP2E1-null mice were treated with TAA (200 mg/kg of body weight, single, i.p.) at 6 weeks of age, and toxicity examined 24 and 48 h after TAA treatment. Relative liver weights of CYP2E1-null mice were significantly different at 24 h compared to wild-type mice (p<0.01). Serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and lactate dehydrogenase in CYP2E1-null mice were significantly different at both time points compared to wild-type mice (p<0.01). Histopathological examination showed CYP2E1-null mice represented no hepatototoxic lesions, in clear contrast to severe centriobular necrosis, inflammation and hemorrhage at both time points in wild-type mice. Marked lipid peroxidation was only limited to wild-type mice (p<0.01). Similarly, TNF-α, IL-6 and glutathione peroxidase mRNA expression in CYP2E1-null mice did not significantly differ from the control levels, contrasting with the marked alteration in wild-type mice (p<0.01). Western blot analysis further revealed no increase in iNOS expression in CYP2E1-null mice. Taken together, we conclude CYP2E1-null mice show lower tumor incidence and multiplicity in DEN-induced hepatocarcinogenesis and no acute damage in TAA-induced hepatotoxicity compared to wild-type mice. And it suggests high frequency of tumors in wild-type mice could be associated with the increase of apoptosis in early time, and severe hepatic damage could be associated with increased oxidative stress.