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The Carcinogenicity of Small Amounts of N-Hydroxy-2-acetylaminofluorene and Its Cupric Chelate in the Rat^*

James A. Miller, Makoto Enomoto and Elizabeth C. Miller

( McArdle Memorial Laboratory for Cancer Research, and Department of Pathology, Medical School, University of Wisconsin, Madison, Wisconsin)

The carcinogenic metabolite of 2-acetylaminofluorene (AAF), N-hydroxy-2-acetylaminofluorene (N-hydroxy-AAF), was active at relatively low doses in the induction of mammary carcinomas and subcutaneous sarcomas in the rat. The intraperitoneal injection of 4.2 mg. of N-hydroxy-AAF into weanling rats caused mammary carcinomas to develop in ten of seventeen rats by 22 weeks. AAF at higher doses was shown previously to be considerably less active than equimolar doses of N-hydroxy-AAF in the induction of mammary carcinomas under similar conditions. Young male rats which received a single subcutaneous injection of 3.2 mg. of N-hydroxy-AAF developed no tumors at the injection site by 6 months. However, the same amount of N-hydroxy-AAF, injected subcutaneously in the form of the poorly soluble cupric chelate, caused a high incidence of sarcomas within 5 months. Repeated subcutaneous injections of AAF, cupric oxide, and cupric acetate induced no tumors by 8 months, even though the total amounts of these compounds which were injected were 6 times the molar level of the single injection of the cupric chelate of N-hydroxy-AAF. Analyses of the subcutaneous injection sites demonstrated that over 60 per cent of the cupric chelate of N-hydroxy-AAF was retained at the site for 2 weeks, whereas none of the injected N-hydroxy-AAF was detectable in the subcutaneous tissue 1 day later. These data constitute additional evidence that N-hydroxy-AAF is a proximal carcinogenic metabolite of AAF in the rat.

^* This investigation was supported by Grant C355 of the National Institutes of Health, United States Public Health Service; a grant from the Jane Coffin Childs Memorial Fund for Medical Research; and by the Alexander and Margaret Stewart Trust Fund.

On leave from the Department of Pathology, University of Tokyo. International Postdoctorate Research Fellow, U.S. Public Health Service, 1961.

Received 8/10/62.