CHRONIC TOXICITY STUDIES OF 5-(2-PYRAZINYL)-4-METHYL-1,2-DITHIOLE-3-THIONE, A POTENTIAL CHEMOPREVENTIVE AGENT

The synthetic compound Oltipraz, 5-(2-pyrazinyl)-4-methyl-1,2-dithiole -3-thione, is related to the 1,2-dithiolthiones naturally found in cru ciferous vegetables, the consumption of which has been epidemiological ly associated with reduced frequency of colorectal cancers. Oltipraz h as shown chemopreventive efficacy in numerous laboratory epithelial ca ncer models and is a potential chemopreventive, antimutagenic compound that specifically induces Phase II enzymes. Thirteen-week and 1-year toxicity studies in rats and dogs were performed to characterize the t oxicities of the compound at high dosages and to support potential fur ther development as a chemopreventive agent in clinical trials. Admini stration to rats by gavage for 13 weeks at dosages of 5 and 50 mg/kg/d ay and for 52 weeks at dosages of 10, 30, and 60 mg/kg/ day produced e ffects on the liver and on clinical chemistry and hematology parameter s. Absolute and relative liver weight increases correlated with diffus e hypertrophy in the mid- and high-dose males and centrilobular hypert rophy in the high-dose females. Granularity of hepatocyte cytoplasm wa s also observed. These anatomical findings were associated with dose-a ssociated slight increases in albumin, total protein, and cholesterol in the males and a moderate increase in cholesterol only in the female s. In addition, slight decreases in erythrocyte count, hemoglobin, and hematocrit and reticulocyte elevations occurred. The no effect dose w as considered 10 mg/kg/day. Administration by capsule to dogs at dosag es of 10 and 100 mg/kg/day for 13 weeks and of 5, 15, and 60 mg/kg/day for 52 weeks also produced effects on the same endpoints noted in the rodent studies. in the 13-week study, precipitate was observed in the bile canaliculi, and gonadal atrophy and increased pituitary weights occurred in the males. Cholesterol and alkaline phosphatase activity w ere slightly elevated in both studies. Decreased hematology parameters in the 13-week study also occurred. The no effect dose was considered to be 5 mg/kg/day. Oltipraz is being carefully evaluated in clinical trials as a potential antimutagenic compound. (C) 1997 Society of Toxi cology.