Non-alcohol dehydrogenase-mediated metabolism of methylazoxymethanol in the deer mouse, Peromyscus maniculatus.
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.
D000426:Alcohol Dehydrogenase; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D001391:Azo Compounds / Q000378:metabolism*; D002250:Carbon Radioisotopes; D004247:DNA / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives / Q000032:analysis; D007553:Isotope Labeling / Q000379:methods; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008746:Methylazoxymethanol Acetate / Q000378:metabolism*; D010542:Peromyscus / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology
D001391:Azo Compounds; D002250:Carbon Radioisotopes; D011720:Pyrazoles; D008746:Methylazoxymethanol Acetate; D006147:Guanine; C008450:7-methylguanine; D004247:DNA; C008449:O-(6)-methylguanine; D000429:Alcohol Oxidoreductases; D000426:Alcohol Dehydrogenase