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 al cohol dehydrogenase (ADH) activates methylazoxymethanol (MAM) in the m ouse 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 t umor-susceptible (SWR/J) and -resistant (AKR/J) mice. Minimal reductio n 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 c apable of sustaining NAD(+) reduction with MAM, although at very low l evels. Despite minimal reactivity with MAM, however, mouse cytosols di d effectively reduce NAD(+) in the presence of the common ADH subrates ethanol and benzyl alcohol. NAD(+)-coupled oxidation of benzyl alcoho l was significantly higher (two- to threefold, p < 0.05) in mouse colo n cytosols compared to activity present within corresponding rat tissu es. Incubation of colon and liver cytosols with the ADH-3 inhibitor 4- methylpyrazole markedly (95-100% of controls) reduced ethanol oxidatio n in both strains. However, 4-methylpyrazole was a less effective inhi bitor of benzyl alcohol oxidation in AKR/J colons, suggesting a differ ent ADH isoform complement. An opposite inhibition pattern of benzyl a lcohol oxidation was seen in the liver, where 4-methylpyrazole produce d a greater inhibition in SWR/J mice. These studies suggest that the m etabolism of the proximate mutagen MAM occurs by processes in the mous e that are independent of ADH. (C) 1998 Society of Toxicology.