Formation of O⁶-Methylguanine by Alkylation of Rat Liver, Colon, and Kidney DNA following Administration of 1,2-Dimethylhydrazine

Summary

The alkylation of DNA in the liver, kidney, and colon was measured at varying times after administration of 1,2-dimethylhydrazine to rats. DNA was alkylated to a much greater extent in the liver than in the kidney or the colon after a dose of 200 mg/kg body weight given either by i.p. or s.c. injection. The level of alkylation in the liver was only slightly affected by the route of administration, but alkylation of kidney DNA was greater after s.c. injection than after i.p. injection, whereas the reverse was the case in the colon. A number of methylated purines were detected in hydrolysates of DNA isolated from rats given [¹⁴C]-1,2-dimethylhydrazine. These included 7-methylguanine, O⁶-methylguanine, 3-methyladenine, 1-methyladenine, and 7-methyladenine. The relative amounts of these products were consistent with the hypothesis that alkylation was mediated via the metabolism of 1,2-dimethylhydrazine to an alkylating species similar to that generated by dimethylnitrosamine and N-methyl-N-nitrosourea. O⁶-Methylguanine was formed in the colon DNA in substantial amounts after injection of the 1,2-dimethylhydrazine and was not lost rapidly from the DNA. However, O⁶-methylguanine was present in greater amounts in the liver than in the colon or kidney at all times examined after the 1,2-dimethylhydrazine dose of 200 mg/kg body weight. Since the liver is not a target organ for 1,2-dimethylhydrazine carcinogenesis, it is apparent that factors other than the production of O⁶-methylguanine must be of importance in tumor initiation. The findings are discussed in relation to the hypothesis that it is the production and persistence throughout DNA replication of O⁶-methylguanine that may be the initiator of neoplasia by those carcinogens that yield methylating agents.