Toxicity and metabolism in mice of 2,6-dithiopurine, a potential chemopreventive agent.
2,6-Dithiopurine (DTP) has been proposed as a possible chemopreventive agent because of its facile reaction with the electrophilic ultimate carcinogen, benzo[a]pyrene diol epoxide, and other reactive electrophiles. Previous studies in mouse skin indicated almost complete inhibition of benzo[a]pyrene diol epoxide-induced tumorigenesis by DTP, suggesting the possible utility of this compound as a chemopreventive agent. However, little is known of the metabolism of DTP or of its possible long-term toxicity. Mice were fed diets containing up to 4% DTP in AIN-76A for a period of 7 weeks, and possible toxicity was monitored by weight gain and histopathological examination of all major tissues. No toxicity was observed at any dose of DTP. DTP was found to be a good substrate in vitro for two enzymes known to metabolize 6-mercapto-purine: xanthine oxidase and thiopurine methyltransferase. The in vitro metabolites were 2,6-dithiouric acid and an apparent monomethylated derivative, respectively. In vivo, the major urinary metabolite was 2,6-dithiouric acid, which attained levels as high as 34 mM in the urine of mice receiving the 4% DTP diet. DTP was also excreted unchanged in the feces and urine. DTP, 2,6-dithiouric acid, and an unidentified, relatively nonpolar metabolite were also detected in the serum of experimental animals. Although large interindividual variation in the serum DTP concentration was found, there was a dose-dependent increase in serum DTP as the dietary level of DTP was increased. These results suggest that neither toxicity nor metabolism will severely limit the utility of DTP as a chemopreventive agent.
D000465:Algorithms; D000818:Animals; D016588:Anticarcinogenic Agents / Q000378:metabolism* / Q000633:toxicity*; D001711:Biotransformation; D004032:Diet; D005243:Feces / Q000737:chemistry; D005260:Female; D007274:Injections, Intraperitoneal; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D018632:Mice, Inbred SENCAR; D011687:Purines / Q000378:metabolism* / Q000633:toxicity*; D015430:Weight Gain / Q000187:drug effects; D014969:Xanthine Oxidase / Q000378:metabolism
D016588:Anticarcinogenic Agents; D011687:Purines; C070898:2,6-dithiopurine; D014969:Xanthine Oxidase; D008780:Methyltransferases; C022745:thiopurine methyltransferase