© 1997 Oxford University Press
research-article |
Chronic Toxicity Studies of 5-(2-Pyrazinyl)-4-methyl-l,2-dithiole-3-thione, a Potential Chemopreventive Agent1
*National Cancer Institute, Chemoprevention Branch Bethesda, Maryland 20892
Southern Research Institute Birmingham, Alabama 35205
MPI Research Mattawan, Michigan 49071
§Hoffman LaRoche Nutley, New Jersey 07003
Received May 1, 1996; accepted September 10, 1996
The synthetic compound Oltipraz, 5-(2-pyraziny1)-4-methyl-1,2- dithiole-3-thione, is related to the 1,2-dithiolthiones naturally found in cruciferous vegetables, the consumption of which has been epidemiologically associated with reduced frequency of colorectal cancers. Oltipraz has shown chemopreventive efficacy in numerous laboratory epithelial cancer 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 toxicities of the compound at high dosages and to support potential further development as a chemopreventive agent in clinical trials. Administration to rats by gavage for 13 weeks at dosages of 5 and 50 mg/kg/day and for 52 weeks at dosages of 10, 30, and 60 mg/kg/ day produced effects on the liver and on clinical chemistry and hematology parameters. Absolute and relative liver weight increases correlated with diffuse hypertrophy in the mid- and highdose males and centrilobular hypertrophy in the high-dose females. Granularity of hepatocyte cytoplasm was also observed. These anatomical findings were associated with dose-associated slight increases in albumin, total protein, and cholesterol in the males and a moderate increase in cholesterol only in the females. In addition, slight decreases in erythrocyte count, hemoglobin, and hematocrit and reticulocyte elevations occurred. The no effect dose was considered 10 mg/kg/day. Administration by capsule to dogs at dosages 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 were 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.