ARYL RADICAL FORMATION DURING THE METABOLISM OF ARYLHYDRAZINES BY MICROSOMES

Many arylhydrazines are genotoxins, although the mechanism of their ge notoxicity is unknown. Previous studies have shown that arylhydrazines are metabolized to arenediazonium ions, which produce C8-arylguanine adducts in DNA suggesting the intermediacy of an aryl radical. Here we have looked for the formation of aryl radicals from arylhydrazines an d microsomes by ESR spin trapping. Only hydroxyl radicals are trapped upon incubation of p-methylphenylhydrazine with rat liver microsomes a nd 5,5-dimethyl-1-pyrroline N-oxide (DMPO). However, hydroxyl and aryl radicals were trapped upon incubation of p-(methoxy-methyl)phenylhydr azine with rat liver microsomes. Evidence for hydroperoxyl radical for mation was also obtained. In contrast, when either of these substrates was incubated with microsomes from C50 cells, aryl and hydroxyl radic als were trapped. The ESR signal intensity of the spin-trapped aryl ra dicals parallels the extent of C8-arylguanine formation in DNA, and th erefore, the aryl radical is likely the intermediate responsible for C 8-arylguanine adduct formation. Aryl radicals and C8-arylguanine adduc ts may be related to the genotoxicity of arylhydrazines and related co mpounds that are oxidatively metabolized to arenediazonium ions, the p recursor to aryl radicals, including arylalkyl nitrosamines, arylazo c ompounds, and triazenes.