Effect of exogenous beta-glucuronidase on the carcinogenicity of 1,2-dimethylhydrazine in rats: evidence that carcinogenic intermediates form conjugates and act through their subsequent enzymatic release.

Abstract

Albino, outbred 3-month-old rats were given a single s.c. dose of 1,2-dimethylhydrazine dihydrochloride (DMH; 100 mg/kg) and, 6 or 24 h later, an i.v. dose of bovine liver beta-glucuronidase (3 X 10(4) Fishman units). After this treatment, the incidence of tumours of the large intestine and Zymbal gland, and of cystocholangiomas was similar to that found in rats treated with DMH alone; the incidence of malignancies in various other tissues was considerably higher than that in rats treated only with DMH, especially in animals exposed to beta-glucuronidase 24 h after administration of DMH. beta-Glucuronidase itself had no carcinogenic activity. The broadening of the spectrum of malignant tumours produced in DMH-treated rats by administration of beta-glucuronidase indicates that the carcinogenic effect of DMH may be exerted through formation of comparatively stable conjugates of its metabolites and their enzymic release in target tissues. The approach used in this study could be helpful in investigating the formation of conjugates from other carcinogens.