Protection by 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) against the hepatotoxicity of aflatoxin B₁ in the rat

A new chemoprotective agent, oltipraz, was evaluated for alleviation of aflatoxin B₁-induced hepatotoxicity. Male F344 rats were fed a diet supplemented with 0.075% oltipraz and compared to rats fed the purified diet (AIN) alone. Rats were fed these diets for 1 week prior to treatment with aflatoxin B₁ (AFB₁) and throughout the experimental period. AFB₁ was administered to rats by gavage in single doses ranging from 0.25 to 10 mg/kg body weight for acute toxicity studies and in multiple doses of 0.25 mg/kg, 5 days/week, for 2 weeks for subchronic toxicity studies. The latter protocol constitutes a tumorigenic dosing regimen. In an acute toxicity study, pretreatment with oltipraz reduced from 83 to 36% the mortality produced by 10 mg/kg AFB₁. Oltipraz significantly suppressed the elevated serum levels of alanine amino transaminase and sorbitol dehydrogenase induced by sublethal doses of AFB₁. In subchronic toxicity studies, the AFB₁-treated rats fed AIN diet failed to gain weight over the 2-week treatment period and their liver weights were severely depressed. In contrast, the rats fed the oltipraz supplemented diet maintained a high rate of growth during AFB₁ treatment. The subchronic AFB₁ treatment regimen also resulted in over 75% loss of prelabeled [³H]thymidine from the liver while oltipraz supplementation largely prevented this loss. Taken together, these results indicate that oltipraz is very effective in ameliorating the toxic effects of AFB₁ in rats.