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Biochemical and Pathological Effects of Methylazoxymethanol Acetate, a Potent Carcinogen¹

Divisions of Pharmacology and Cytology, Sloan-Kettering Institute for Cancer Research, New York, New York 10021

Methylazoxymethanol acetate is known to induce tumors in rodents. Effects produced by a single nonlethal dose on nucleic acid and protein synthesis have been investigated in rat and mouse liver, small intestine, and kidney, the 3 organs most susceptible to carcinogenesis. The agent induced early inhibition of thymidine incorporation into DNA of rat tissues. Rat liver was most sensitive to this effect and was the only organ to show marked inhibition of RNA and protein synthesis. In mice, liver was more sensitive than small intestine or kidney and exhibited an inhibition of RNA and protein synthesis; there were no changes observed in small intestine or kidney. Pathological effects of methylazoxymethanol acetate have been studied by light and electron microscopy. In rats, 6 hr after treatment there was minimal focal necrosis in liver; duodenum and colon, however, showed marked karyorrhexis in crypt epithelium. Intestinal recovery was evident by 1 week, whereas hepatic nuclear changes, consisting of enlarged and irregular nuclei, were detectable months later. Microsegregation in rat hepatic cell nucleoli was evident within 1 hr after treatment, prior to inhibition of nuclear RNA synthesis; the nucleolar change persisted for several months. Mouse liver showed necrosis while duodenal changes were minimal. Kidneys of both species appeared normal at all times. The relationships between inhibition of the synthesis of the various macromolecules, the pathological effects, and carcinogenesis are discussed.

¹ Aided by Grant CA 08748 from the National Cancer Institute, USPHS. Presented in part at the 60th Annual Meeting of the American Association for Cancer Research, March 23 to 25, 1969.

² Present address: Department of Experimental Pathology and Cancer Research, University of Leeds, Leeds 2, England.

Received 6/23/69. Accepted 8/25/69.

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