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 diet epoxide, and other reactive electrophi les. Previous studies in mouse skin indicated almost complete inhibiti on of benzo[a]pyrene diol epoxide-induced tumorigenesis by DTP, sugges ting 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 w eight gain and histopathological examination of all major tissues. No toxicity was observed at any dose of DTP. DTP was found to be a good s ubstrate in vitro for two enzymes known to metabolize 6-mercaptopurine : xanthine oxidase and thiopurine methyltransferase. The in vitro meta bolites were 2,6-dithiouric acid and an apparent monomethylated deriva tive, respectively. In vivo, the major urinary metabolite was 2,6-dith iouric acid, which attained levels as high as 34 mM in the urine of mi ce receiving the 4% DTP diet. DTP was also excreted unchanged in the f eces and urine, DTP, 2,6-dithiouric acid, and an unidentified, relativ ely nonpolar metabolite were also detected in the serum of experimenta l animals. Although large interindividual variation in the serum DTP c oncentration was found, there was a dose-dependent increase in serum D TP as the dietary level of DTP was increased. These results suggest th at neither toxicity nor metabolism will severely limit the utility of DTP as a chemopreventive agent.