- Hiroki Yoshioka (College of Pharmacy, Kinjo Gakuin University / Faculty of Nutrition, Kobe Gakuin University / firstname.lastname@example.org)
1) College of Pharmacy, Kinjo Gakuin University , 2) Faculty of Nutrition, Kobe Gakuin University
Carbon tetrachloride (CCl4) is a well-known hepatotoxic chemical. Exposure to CCl4 produces free radicals, which induce oxidative stress and cause hepatic injury. We demonstrated previously that pretreatment with zinc (Zn), which induces metallothionein (MT) expression, prevents CCl4-induced lethal toxicity in a dose-dependent manner. While MT has been suggested as a possible hepatoprotective protein, its mechanism of protection remains unknown. In the current study, we evaluated the protective mechanism of MT, an endogenous scavenger of free radicals, against CCl4-induced toxicity through subcutaneous administration of 50 mg/kg Zn (as ZnSO4) once daily for three consecutive days, prior to a single intraperitoneal injection of 4 g/kg CCl4 in male ddY mice. Our results showed that Zn pretreatment significantly decreased aspartate aminotransferase and total cholesterol levels, 6-hr after CCl4 injection, as well as lipid peroxidation. Moreover, CCl4-induced hepatic calcium level was downregulated by pretreatment with Zn while Zn-induced MT expression decreased by more than 500 μg/g liver (43%) in the Zn + CCl4-treated group, implying that MT was consumed by CCl4-induced free radicals. These findings suggest that prophylaxis with Zn protects mice from CCl4-induced acute hepatotoxicity, presumably by inducing the expression of free radical-scavenging MT.