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Methylation of DNA guanine during the course of induction of liver cancer in hamsters by hydrazine or dimethylnitrosamine
1Department of Community and Environmental Medicine, University of California, Irvine, Cambndge, MA 02139, USA
2Present address:Chevron Environmental Health Center P0 Box 4054, Richmond, CA 94804, USA
3University of California, Irvine, Southern Occupational Health Center, Irvine, CA, Cambndge, MA 02139, USA
4Toxic Hazards Research Unit, University of California, Irvine, Wright-Patterson Air Force Base, OH, Cambndge, MA 02139, USA
5Present address: Rte 1, Box 2897, Spring City, TN 37381, USA
6Present address:Illinois Institute of Teclmology Research Institute 10 W. 35th St, Chicago, IL 60619, USA
7Department of Applied Biological Sciences, Massachusetts Institute of Technology, Cambndge, MA 02139, USA
8Present address:Mallory Institute of Pathology 784 Massachusetts Avenue, Boston University, Boston, MA 02118, USA
9whom reprint requests should be sent
Hydrazine is carcinogenic to the mouse and rat, but three earlier studies have reported no carcinogenicity of hydrazine in the hamster. Administration of hydrazine to mice, rats and hamsters results in rapid methylation of liver DNA guanine for which endogenous formaldehyde appears to be the source of the methyl moiety. Hamsters were given hydrazine sulfate at 170, 340 and 510 mg/I in the drinking water for 2 years [average dose of 4.6, 8.3 and 10.3 mg hydrazine (free base)/kg body wt over the 2-year period], during which levels of methylation of DNA guanine in liver, kidney and lung, and histopathologic examinations of these tissues were carried out; dimethylnitrosamine, as a positive control, was administered at 10 mg/I in the drinking water (average dose of 1.1 mg/kg body wt over the 4-month measurement period). Both 7-methylguanine and 06 were readily detec table at 6 months exposure in hamsters given hydrazine or dimethylnitrosamine; in hydrazine-treated animals only trace amounts of these bases could be detected after 12 months ex-posure; these bases were again detected in liver DNA at ex-posure times of 18 and 24 months. Hepatocellular carcinomas were observed in hamsters treated at the highest dose of hydrazine sulfate after 78 weeks of exposure; the incidence of liver cancer was dose-related over the course of the ex-periinent: 32% for hamsters exposed to 510 mg hydrazine sulfate/I, 12% for 340 mg/I and none at 170 mg/I. Hamsters given dimethylnitrosamine developed high levels of 7-methyl-guanine and even higher levels of O6 and both liver cholangiocellular carcinomas (73% incidence), as reported before, and hepatocellular carcinomas (27% in-cidence), a new finding. These results demonstrate for the first time that hydrazine is a liver carcinogen in the hamster and provide new information regarding the accumulation of DNA damage during the entire induction period for the car cinomas.
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  S. M. Hussain and J. M. Frazier Cellular Toxicity of Hydrazine in Primary Rat Hepatocytes Toxicol. Sci., October 1, 2002; 69(2): 424 - 432. [Abstract] [Full Text] [PDF]
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