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Carcinogenicity of Deuterium-labeled 1,2-Dimethylhydrazine in Mice¹

Department of Chemical Carcinogenesis, Cancer Research Centre, 115478 Moscow, USSR [V. S. T., N. S. L., Y. D. P.]; Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195 [W. P. G., S. D. N.]; Food and Drug Administration, Rockville, Maryland 20857 [P. S. H.]; and Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility, Frederick, Maryland 21701 [L. K. K.]

To study the effect of deuterium substitution on the carcinogenicity of 1,2-dimethylhydrazine (DMH) in mice, two comparisons were made between DMH and its fully methyl-deuterated analogue, [²H₆]DMH. In a lifetime study with the CBA strain, groups of 19–30 animals of each sex were dosed s.c. weekly with 8 mg/kg of either DMH or [²H₆]DMH for 8, 16, or 32 weeks. In the second study, female CF-1 mice were given DMH or [²H₆]DMH in 10 weekly s.c. doses of 12 mg/kg each (13.2 mg/kg for [²H₆]DMH) and examined for colon tumors 36 weeks after the first dose. Deuteration significantly decreased tumor incidence in the colon of males (P < 0.01) and the anal tissue of both sexes (P < 0.05) but increased that of hepatomas and lung tumors in males (P < 0.01). Substrate deuteration did not significantly affect overall incidence of any other tumor type, however, including hemangioendotheliomas and kidney tumors in both sexes, as well as colon, uterine, ovarian, liver, and lung tumors in females. The results indicate that C-H bond breakage is kinetically important in the activation of DMH to its ultimately carcinogenic form in organs such as the male colon (relative risk in DMH-verzus [²H₆]DMH-treated animals 6), and that inhibition of this process by substrate deuteration allows a diversionary mechanism having a smaller isotope effect to become relatively more extensive. The qualitatively different effect in other organs (e.g., kidney, relative risk 1) supports recent suggestions that the net mechanism of activation can differ from one target tissue to another, possibly by striking a different balance between parallel metabolic pathways. The lack of a significant isotope effect on overall colon tumor incidence in females of either strain suggests that differences in relative importance among competing enzymes may also be responsible for sexual dimorphism in tumor induction by DMH.

¹ This study was arranged in part through the US-USSR Medical Science and Public Health Cooperative Agreement in 1979.

² To whom requests for reprints should be addressed, at NCI-FCRF, Building 538, Frederick, MD 21701.

Received 7/27/87. Revised 10/21/87. Revised 12/28/87. Accepted 1/15/88.

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