Mutagenicity of methylazoxymethanol acetate in the presence of alcohol dehydrogenase, aldehyde dehydrogenase, and rat liver microsomes in Salmonella typhimurium His G46.
Methylazoxymethanol (MAM) is the short-lived toxic and carcinogenic aglycone of cycasin, a natural component of the cycad plant. In the present study, the stable acetate ester of MAM, MAM acetate, was tested in combination with porcine liver esterase and Salmonella typhimurium His G46 to study the comparative mutagenicity of this compound in the presence of rat hepatic alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and rat liver microsomes. In the presence of rat liver microsomes and an NADPH-generating system, mutagenicity of MAM acetate was not significantly altered. However, addition of rat liver 105,000g supernatant fraction and/or NAD+ significantly increased the number of his+ revertants above control. A concentration-dependent increase in mutagenicity of MAM acetate was observed for NAD+ from 50 to 200 microM, while NADP+ caused a decrease in mutagenicity of MAM acetate in this same concentration range. Pyrazole (100-500 microM) had no significant effect on mutagenicity of MAM acetate in the presence of rat liver 105,000g supernatant, while disulfiram at 500 microM resulted in a significant decrease in mutagenicity of MAM acetate. The results of this study implicate ALDH as essential in activation of MAM acetate to a mutagenic species in this system, while the role of ADH and microsomes appears to be minimal.
U.S. Environmental Protection Agency, Office of Pesticide Programs, Washington, DC 20460.
T F
TF
McMahon
M L
ML
Cunningham
D000426:Alcohol Dehydrogenase / Q000378:metabolism*; D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D003600:Cytosol / Q000378:metabolism; D004221:Disulfiram / Q000494:pharmacology; D004950:Esterases / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D008746:Methylazoxymethanol Acetate / Q000378:metabolism / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology*; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D012486:Salmonella typhimurium / Q000187:drug effects*; D013552:Swine
D009153:Mutagens; D011720:Pyrazoles; D009243:NAD; C031280:pyrazole; D009249:NADP; D008746:Methylazoxymethanol Acetate; D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase; D004950:Esterases; D004221:Disulfiram