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N-Hydroxy Metabolites of 2-Acetylaminophenanthrene and 7-Fluoro-2-acetylaminofluorene as Proximate Carcinogens in the Rat¹

McArdle Laboratory for Cancer Research, Medical Center, University of Wisconsin, Madison, Wisconsin, and Chemistry Research Laboratory, Department of Surgery, School of Medicine, University of Washington, Seattle, Washington

N-Hydroxy-7-fluoro-2-acetylaminofluorene (N-hydroxy-7-fluoro-AAF) and N-hydroxy-2-acetylaminophenanthrene (N-hydroxy-AAP) were identified as urinary metabolites of 7-fluoro-2-acetylaminofluorene and 2-acetylaminophenanthrene, respectively, in the rat.

When administered as 0.010–0.012% of the diet for 10–15 weeks N-hydroxy-7-fluoro-AAF proved to be a much more potent carcinogen for the rat than 7-fluoro-AAF. The N-hydroxy derivative produced high incidences of squamous cell carcinomas of the forestomach, adenocarcinomas of the small intestine, carcinomas of the liver, and carcinomas of the mammary gland (females). In addition, this compound induced significant incidences of carcinomas of the ear duct gland and urinary bladder. On an average each rat had more than 2 primary tumors of different tissue origins. Under these conditions 7-fluoro-AAF induced primarily liver and mammary carcinomas; even at these sites the amide was less active than the N-hydroxy derivative.

When administered by s.c. injection in young female rats N-hydroxy-AAP induced sarcomas at the site of injection and a high incidence of mammary carcinomas. Under these conditions AAP induced only a few mammary carcinomas and no sarcomas.

Repeated i.p. injections of the N-hydroxy derivatives of aniline and N-ethylaniline (total doses of 58 and 72 mg) did not result in mammary tumor induction in female rats.

These data, in addition to those reported earlier, indicate that N-hydroxylation is of general importance in the neoplastic processes induced by carcinogenic aromatic amides and amines.

Syntheses are reported for the following new compounds: N-hydroxy-7-fluoro-2-acetylaminofluorene and N-hydroxy-2-acetylaminophenanthrene.

¹ This investigation was supported at the University of Wisconsin by a research training grant, CRTY-5002, and by Program-Project Grant CA-07175 of the National Cancer Institute, USPHS; by a grant from the Jane Coffin Childs Memorial Fund for Medical Research; and by the Alexander and Margaret Stewart Trust Fund. It was supported at the University of Washington (T. Lloyd Fletcher) by Research Grant CA-01744 and Career Development Award 5-K3-GM-14,991 of the NIH, USPHS.

Received 1/28/66. Accepted 5/17/66.