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1'-Hydroxysafrole, a Proximate Carcinogenic Metabolite of Safrole in the Rat and Mouse¹

McArdle Laboratory for Cancer Research, University of Wisconsin Medical Center, Madison, Wisconsin 53706

When fed as 0.5% of the diet for 8 to 10 months, 1'-hydroxysafrole induced a high incidence of hepatocellular carcinomas in male rats; safrole induced only a low incidence under these conditions. 1'-Acetoxysafrole, because of its toxicity, was fed to rats at only 0.6 the molar level of the above compounds. These rats did not develop hepatic tumors, but all of those that survived at least 6 months developed multiple papillomas of the forestomach; squamous cell carcinomas were found in the forestomachs of two of these rats. A few isolated papillomas of the forestomach were observed in rats fed 1'-hydroxysafrole.

Eighty-four and 82%, respectively, of male mice given injections of 1'-hydroxy- or 1'-acetoxysafrole at 1 to 21 days of age (total dose, 9.5 µ;moles) and killed at 12 to 14 months of age had liver tumors; the incidences were 40% for male mice given injections of safrole and 8% for the controls. Of the adult male mice fed 0.4 or 0.5% of safrole for 13 months and killed at 16 months, 30% had liver tumors; the incidence was 11% in the controls. Some liver tumors also developed in adult male mice fed 1'-hydroxysafrole, but the number of survivors was low. All of these liver tumors were diagnosed as highly differentiated hepatic carcinomas. Between the 14th and 16th months, 46% of the mice that were fed 1'-hydroxysafrole and that survived at least 12 months developed sarcomas, most of which were diagnosed as angiosarcomas, in the interscapular region; only two safrole-fed mice and one control mouse developed tumors at this site.

Twenty s.c. injections of 18.6 µmoles each of 1'-acetoxysafrole or 1'-hydroxysafrole induced sarcomas in 30 and 8%, respectively, of adult male rats. These sarcomas were observed 12 to 18 months after the 1st injection.

Skin tumors did not develop in mice treated topically 14 times with 1.8 µmoles of safrole; its 1'-hydroxy, 1'-methoxy, or 1'-acetoxy derivatives; or the corresponding 2',3'-dihydrosafrole derivatives and then given twice weekly applications of phorbol-12,13-didecanoate.

On the basis of the above data and our finding that a conjugate of 1'-hydroxysafrole is excreted in the urine of rats and mice given p.o. or i.p. safrole, we conclude that 1'-hydroxysafrole is a proximate carcinogenic metabolite of safrole.

¹ This work was supported by Grants CA-07175 and CRTY-5002 of the National Cancer Institute, USPHS, and by a grant from the Jane Coffin Childs Memorial Fund for Medical Research.

² Present address: Oakdale Pharmacology Center, University of Iowa Medical School, Iowa City, Iowa.

Received 10/ 5/72. Accepted 12/11/72.

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