The role of alcohol dehydrogenase in the metabolism of the colon carcinogen methylazoxymethanol.
The aim of this study was to determine whether the cytosolic enzyme alcohol dehydrogenase (ADH) activates methylazoxymethanol (MAM) in the mouse colon and whether differential tumor susceptibility in the mouse is dependent, in part, on strain-related differences in MAM metabolism by ADH. Liver and colon cytosols were isolated from 7-week-old male tumor-susceptible (SWR/J) and -resistant (AKR/J) mice. Minimal reduction of NAD+ was found in colon cytosols from AKR/J mice at the highest concentration (2 mM) of MAM tested. In liver cytosols, only SWR was capable of sustaining NAD+ reduction with MAM, although at very low levels. Despite minimal reactivity with MAM, however, mouse cytosols did effectively reduce NAD+ in the presence of the common ADH subrates ethanol and benzyl alcohol. NAD(+)-coupled oxidation of benzyl alcohol was significantly higher (two- to three-fold, p < 0.05) in mouse colon cytosols compared to activity present within corresponding rat tissues. Incubation of colon and liver cytosols with the ADH-3 inhibitor 4-methylpyrazole markedly (95-100% of controls) reduced ethanol oxidation in both strains. However, 4-methylpyrazole was a less effective inhibitor of benzyl alcohol oxidation in AKR/J colons, suggesting a different ADH isoform complement. An opposite inhibition pattern of benzyl alcohol oxidation was seen in the liver, where 4-methylpyrazole produced a greater inhibition in SWR/J mice. These studies suggest that the metabolism of the proximate mutagen MAM occurs by processes in the mouse that are independent of ADH.
Delker
D A
DA
Department of Pharmaceutical Sciences, University of Connecticut, Storrs 06269-2092, USA.
McKnight
S J
SJ
Rosenberg
D W
DW
D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000438:Alcohols / Q000378:metabolism; D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D003106:Colon / Q000378:metabolism*; D000077604:Fomepizole; D008099:Liver / Q000378:metabolism*; D008297:Male; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives* / Q000378:metabolism; D051379:Mice; D008806:Mice, Inbred AKR; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats
D000438:Alcohols; D002273:Carcinogens; D011720:Pyrazoles; D008746:Methylazoxymethanol Acetate; D000077604:Fomepizole; D000426:Alcohol Dehydrogenase; C030667:methylazoxymethanol