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Non-Alcohol Dehydrogenase-mediated Metabolism of Methylazoxymethanol in the Deer Mouse, Peromyscus maniculatus^1,2,

Naylor Dana Institute for Disease Prevention, Valhalla, New York 10595 [E. S. F., N. C., O. S. S., J. H. W.]; Department of Biology, University of South Carolina, Columbia, South Carolina 29208 [M. R. F.]; and Department of Epidemiology and Community Health, Center for the Environmental Health Sciences, Cleveland, Ohio 44106 [G. D. M.]

The concept that alcohol dehydrogenase (ADH) is involved in the metabolism of methylazoxymethanol (MAM) was examined in a model consisting of two strains of the deer mouse, Peromyscus maniculatus, one of which has a normal complement of the enzyme [ADH(+)], and the other, which completely lacks it [ADH(-)]. Both the ADH(+) and the ADH(-) strains rapidly metabolized [¹⁴C]MAM, administered in the form of the acetic acid ester, [¹⁴C]MAMOAc, to ¹⁴CO₂, and the rates and extents of metabolism were virtually identical. Determination of O⁶-methylguanine and 7-methylguanine in liver DNA 6 and 24 hr after MAMOAc (25 mg/kg) administration showed that the levels of DNA methylation induced by the carcinogen were not significantly different in the two strains, indicating that both are capable of the metabolic activation of MAM to methylating species. Pyrazole, a potent inhibitor of ADH, inhibited MAM metabolism as well as liver DNA methylation in the ADH(+) strain; however similar inhibition of these processes also occurred in the ADH(-) strain. 3-Methylpyrazole, a weak or noninhibitor of ADH, also decreased the levels of MAM metabolism in both the ADH(+) and the ADH(-) strains. From these results, we conclude that ADH is not obligatory either in the metabolism or in the metabolic activation of MAM. As a possible alternative to ADH, liver microsomes were examined for their ability to metabolize MAM. In the presence of a NADPH-generating system, liver microsomes from both strains converted [¹⁴C]MAM to ¹⁴CH₃OH and ¹⁴CH₂O, although liver microsomes from the ADH(-) strain were more active in this respect. The microsomal metabolism was sensitive to inhibition by CO as well as to inhibition by pyrazole and 3-methylpyrazole.

¹ Supported in part by Grant CA 31012 from the National Cancer Institute, NIH, Bethesda, MD.

² This paper is dedicated to the memory of Dr. Silvio Emerich Fiala, January 1, 1911 to December 4, 1981.

³ To whom requests for reprints should be addressed.

Received 9/ 6/83. Accepted 4/ 6/84.

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