Role of Formaldehyde in Hydrazine-Induced Methylation of Liver DNA Guanine

摘要

Administration of hydrazine to rodents results in the formation of 7-methyl-guanine and O superscript 6-methylguanine in DNA of liver, and, to a lesser extent, kidney, and lung. The source of the methyl moiety appears to be the one-carbon pool. The role of formaldehyde in this aberrant methylation of the genetic material was investigated in this study. Endogenous levels of formaldehyde in the liver are difficult to alter; administration of hydrazine to rats produced little change in formaldehyde levels in liver, kidney, lung, or brain. Administration of methenamine, a compound which decomposes to ammonia and formaldehyde, increased slightly hydrazine-induced methylation of DNA; methenamine administration itself, without hydrazine, produced a small amount of 7-methylguanine and O superscript 6-methylguanine in rat liver DNA. An in vitro system consisting of rat or hamster liver cell fractions, calf thymus DNA, and Krebs-Ringer phosphate buffer provided a facile means of controlling aldehyde concentrations in studying hydrazine-induced alkylation of DNA. As little as 1 mM hydrazine was able to induce DNA methylation as long as formaldehyde (1 mM) and active liver enzymes were present, no alkylation took place when acetaldehyde was substituted for formaldehyde or when liver fractions were heat-inactivated. The extent of DNA methylated but was dependent on the order in which hydrazine and formaldehyde were allowed to react, suggesting that perhaps more than one reaction product was involved in the methylation process.