title: Methylation status of DNA cytosine during the course of induction of liver cancer in hamsters by hydrazine sulfate.
abstract: Hydrazine, which is toxic and carcinogenic to rodent liver, has been shown to react with endogenous formaldehyde in the liver to form formaldehyde hydrazone (CH2 = N-NH2), an alkylating intermediate that methylates DNA guanine at the N7- and O6-positions. Studies were conducted to investigate the role of chronic hydrazine-induced hepatotoxicity on DNA maintenance methylation (formation of 5-methyldeoxycytosine) and the development of liver cancer. Male Syrian golden hamsters were given hydrazine sulfate (0, 170, 340 and 510 mg/l) in drinking water for 21 months (average dose 0, 4.2, 6.7 and 9.8 mg/kg body wt hydrazine as the free base). Hepatotoxicity was evaluated histologically, and regenerative DNA synthesis and maintenance methylation were measured as the incorporation of [methyl-14C]thymidine into DNA and the methyl moiety of [methyl-3H]methionine into 5-methyldeoxycytosine in DNA, respectively. Methylguanines were detected in liver DNA at the first observation time of 6 months of treatment; levels of these aberrant bases decreased or became undetectable at 14 months, and increased in a dose-related manner for the remainder of the study. DNA adducts persisted in the highest dose group throughout the study, repeating the results of a similar study previously reported by this laboratory (Bosan et al., Carcinogenesis, 8, 439-444, 1987). Linear regression analysis of thymidine and methionine methyl moiety incorporation into liver DNA suggested impairment of maintenance methylation of DNA (5-methyldeoxycytosine) in the middle and high exposure animals. Hepatic adenomas and hepatocellular carcinomas developed in a dose-related manner and were highly correlated to decreased uptake of radiolabel from methionine into DNA 5-methylcytosine. These results are part of a continuing study on alteration of maintenance methylation during hydrazine induction of liver cancer.
authors.affiliation: Department of Community and Environmental Medicine, University of California, Irvine 92697-1825, USA.
authors.forename: B E
authors.initials: BE
authors.lastname: FitzGerald
authors.forename: R C
authors.initials: RC
authors.lastname: Shank
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D006224:Cricetinae; D003596:Cytosine / Q000378:metabolism*; D019175:DNA Methylation; D006834:Hydrazines / Q000633:toxicity*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D013936:Thymidine / Q000378:metabolism
chemical_list: D002273:Carcinogens; D006834:Hydrazines; C029424:hydrazine; D003596:Cytosine; D013936:Thymidine