Effect of dietary antioxidants on dieldrin-induced hepatotoxicity in mice

An increasing number of reports suggest that oxidative stress plays a role in the toxicity of various xenobiotics, including organochlorine pesticides and drugs such as phenobarbital. Antioxidants appear to be protective against the damage induced by an acute dose of endrin, supporting the theory of a role for reactive oxygen in the toxicity of this class of compounds. The current study examined the effects of the dietary administration of vitamin C (400 mg/kg diet) or vitamin E (200 mg DL-alpha-tocopherol acetate/kg diet) on hepatotoxicity induced by subchronic (7 or 28 days) feeding of dieldrin (1, 3 and 10 mg/kg diet) to male B6C3F1 mice. Hepatoxicity induced by feeding of dieldrin for 28 days was evidenced by liver enlargement, hypertrophy of centrolobular hepatocytes, induction of hepatic ethoxyresorufin O-deethylase activity, and increased DNA synthesis in hepatocytes, particularly in centrolobular hepatocytes. Neither vitamin inhibited the dose-dependent increase in liver/body weight ratios, hypertrophy of centrolobular hepatocytes, or induction of hepatic ethoxyresorufin O-deethylase. Vitamin E, however, inhibited hepatic DNA synthesis at all dietary intakes of dieldrin, while vitamin C was inhibitory at 1 and 3, but stimulatory at 10 mg dieldrin per kg diet. The major changes in DNA labeling occurred in the centrolobular zones, but were not consistently inhibited by vitamins C or E. The ability of antioxidant vitamins to inhibit dieldrin-induced hepatic DNA synthesis suggests oxidative stress is involved in the toxicity of this compound; however, the inability of these vitamins to prevent all hepatotoxic changes indicates other factors are also involved.