Metallothionein protects against isoniazid-induced liver injury through the inhibition of CYP2E1-dependent oxidative and nitrosative impairment in mice

Abstract

Oxidative stress mediated by hepatic CYP2E1 during isoniazid (INH) metabolism is considered responsible for INH hepatotoxicity. This study attempts to determine whether metallothionein (MT), a cysteine-rich antioxidant can protect against INH-induced liver injury by using a MT-I/II deficient mouse model (MT−/− mice). MT−/− mice and the corresponding wild-type mice received intragastric administrations of 0, 75, 150 and 300 mg/kg of INH for 15 days. The results showed that 150 and 300 mg/kg of INH induced liver injury in both types of mice, as evidenced by increased liver index and histopathological change of liver vacuolar degeneration. Increased hepatic MDA level and 3-NT expression, and decreased GSH content and SOD activity were also observed in both types of mice, indicating the involvement of oxidative and nitrosative stress. INH treatment upregulated hepatic CYP2E1 expression in both types of mice, and the severity of liver injury was in concert with the elevation of CYP2E1 expression. Comparative analyses revealed liver vacuolar degeneration and oxidative and nitrosative stress were more severe in MT−/− mice than wild-type mice, suggesting the hepatoprotection of MT against INH hepatotoxicity. Taken together, these findings clearly demonstrate that MT protects against INH-induced liver toxicity by ameliorating CYP2E1-dependent oxidative and nitrosative impairment.