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The Metabolism of Methylated Aminoazo Dyes

V. Evidence for Induction of Enzyme Synthesis in the Rat by 3-Methylcholanthrene^*

( McArdle Memorial Laboratory, Medical School, University of Wisconsin, Madison, Wis.)

1. The ability of fortified rat liver homogenates to N-demethylate 3-methyl-4-monomethylaminoazobenzene (demethylase activity) and to reduce the azo linkage of 4-demethylaminoazobenzene (reductase activity) was increased several-fold by the intraperitoneal injection of 0.1 to 10 mg. of 3-methylcholanthrene (MC) 24 hours prior to assay. Significant increases in demethylase activity were obtained by 6 hours.

2. A number of other polycyclic hydrocarbons caused similar increases in demethylase activity, but other closely related hydrocarbons were inactive. There was no correlation between the carcinogenic activities of the hydrocarbons and their effects on the demethylase system. Of a variety of other compounds tested, only the 3,4- and 9,10-quinones of 1,2,5,6-dibenzanthracene were active; a number of other quinones were inactive.

3. The increase in demethylase activity appears to be due to an increase in the amount of enzyme. None of the compounds tested was active in vitro, and no stimulatory or inhibitory factors were detected in livers with high or low activity. The administration of ethionine completely inhibited the response of the demethylase system to MC and prevented further increases in activity in rats previously treated with MC, but it did not alter the enzyme activity already present. Ethionine also prevented the increase in activity of the reductase system due to MC. The inhibition of the response of the demethylase system to MC by ethionine was prevented completely and that of the reductase system partially prevented by the simultaneous administration of methionine.

4. Hypophysectomy and adrenalectomy did not significantly alter the response of the hepatic demethylase and reductase systems to MC.

^* This investigation was supported by Grant C355 of the National Cancer Institute, United States Public Health Service, grant-in-aid N-5 from the American Cancer Society upon recommendation of the National Research Council, Institutional Grant 71 from the American Cancer Society, and an institutional grant from the Alexander and Margaret Stewart Trust Fund. The technical assistance of Miss Marie Hayes in gratefully acknowledged.

Received 2/29/56.

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