Comparative Study on the Indirect Methylation of Liver DNA Guanine by the 1-Carbon Pool in Hepatotoxicity
Hydrazine, H2N-NH2, is widely used in industry and the military; it is acutely toxic to the liver, kidney, and central nervous system. Chronic inhalation of hydrazine produced squamous cell carcinomas of the nasal turbinates in Fischer 344 rats but only at exposures which led to severe rhinitis with focal hyperplasia and squamous metaplasia early in the experiment; Syrian golden hamsters and C57B16 mice did not develop cancers under the same conditions. Biancifiori and Severi (1966) showed that oral administration of hydrazine at growth-depressing doses induced hepatocellular carcinomas and lung adenomas in male rats, pulmonary adenomas in BALB/c/Cb/Se and BALB/c/An/Se mice and pulmonary adenocarcinomas and hepatomas in CBA/Cb/Se mice. Swiss Webster (Crl:CFW(SW)BR) and B6C3Fl(:CrlBR) male mice from Charles River Breeding Lab. in Massachusetts, USA, were fasted overnight and given 0, 5,10,20, or 40 mg hydrazine per kg body weight by intraperitoneal injection and decapitated 24 hr later. Liver DNA was isolated and analyzed by high performance liquid chromatography and fluorescence spectrophotometry for chemical adducts involving the purine bases. A dose related formation of 7-methylguanine and O6-methylguanine was observed in DNA, with little difference between the two strains of mice. Evidence suggests that the hydrazine reacts with endogenous formaldehyde to form a stable intermediate, possibly tetraformyltrisazine, which is metabolized by alcohol and aldehyde dehydrogenases to an active methylating agent. In an experiment similar to the dose-response study, 20 mg hydrazine/kg body wt was given to the two strains of mice, and animals were killed at 24 hr intervals to determine the persistence of these aberrant purines in DNA. The rates of formation of 7-methylguanine and O6-methylguanine and the rates of disappearance of 7-methylguanine from DNA were the same in both strains. The rate of disappearance of the promutagenic base, O6-methylguanine, however, was an order of magnitude slower in the B6C3F1 mouse compared with the Swiss Webster mouse; the half-life of O6-methylguanine in the B6C3F1 mouse liver DNA was greater than 200 hr, while in Swiss Webster mouse liver DNA, it was 17 hr. These results are compared with a similar study in the Syrian golden hamster in which the levels of O6-methylguanine in liver DNA were measured over a 2-yr exposure to hydrazine; the results suggest that the B6C3F1 mouse would be highly susceptible to the hepatocarcinogenicity of hydrazine. This susceptibility is compared with that of other species.
Key wordsHydrazine Dimethylnitrosamine Tetraformyltriazine 7-Methylguanine O6-Methylguanine DNA damage DNA repair Chronic toxicity Methylation of DNA guanine
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