Studies on the Mechanism of Action of Hydrazine-Induced Methylation of DNA Guanne
Rept. for Jun 83-Jun 84,
CALIFORNIA UNIV IRVINE DEPT OF COMMUNITY AND ENVIRONMENTAL MEDICINE
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Hydrazine is a strong reducing agent and is widely used by industry and by the military as a rocket propellant it is a potent hepatotoxin and a weak carcinogen. Hydrazine administration to rodents results is methylation of DNA guanine. The methyl moiety in these aberrant bases can be derived from either methionine or formate however, earlier studies could not provide evidence to support monomethylhydrazine as an important intermediate in this unusual of DNA. It was proposed that formaldehyde hydrazone, CH2-N-NH, which in turn could be metabolically oxidized to the potent methylating agent, diazomethane. Several in vivo studies were carried out to determine the role of aldehydes in the alkylation of DNA in response to hydrazine administration. While tissue levels of acetaldehyde could readily be altered by administration of ethanol, formaldehyde levels were nearly refractory to several techniques designed to raise the concentration of the one-carbon unit in rodent liver. Pretreatment of rats and hamsters with disulfiram, an inhibitor of aldehyde dehydrogenase, sucessfully raised formaldehyde or acetaldehyde levels following administration of methanol or ethanol.