Toxicity and metabolism in mice of 2,6-dithiopurine, a potential chemopreventive agent

W. G. Qing, K. L. Powell, G. Stoica, C. L. Szumlanski, Richard M Weinshilboum, M. C. Macleod

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Abstract

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-mercaptopurine: 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.

Original languageEnglish (US)
Pages (from-to)854-860
Number of pages7
JournalDrug Metabolism and Disposition
Volume23
Issue number8
StatePublished - 1995
Externally publishedYes

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ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Qing, W. G., Powell, K. L., Stoica, G., Szumlanski, C. L., Weinshilboum, R. M., & Macleod, M. C. (1995). Toxicity and metabolism in mice of 2,6-dithiopurine, a potential chemopreventive agent. Drug Metabolism and Disposition, 23(8), 854-860.