HYDRALAZINE AND OTHER HYDRAZINE DERIVATIVES AND THE FORMATION OF DNA-ADDUCTS

Previous work has demonstrated that hydrazine after formylation to its corresponding hydrazone may be activated both in vivo and in vitro to a methylating intermediate resulting in the formation of O-6-methyl- and N-7-methylguanines in DNA. Incubation of calf thymus DNA with the hydrazine derivative, hydralazine, and formaldehyde resulted in the pr oduction of N-7-methylguanine and two aberrant bases in DNA. These bas es were separated by strong cation-exchange high-performance liquid ch romatographic fractionation of neutral thermal hydrolysates. Administr ation of hydralazine to rats resulted in the formation of N-7-methylgu anine in liver DNA, but the two unknown bases observed in the in vitro experiment could not be demonstrated in vivo. In contrast to hydrazin e, administration of hydralazine resulted in the methylation of DNA on ly at doses approaching the LD50, suggesting that formylation does not represent a significant mechanism for hydralazine toxicity in the sys tem described. Hydralazine in combination with formaldehyde resulted i n the formation of triazolophthalazine, a metabolite which has been ch aracterized in man. The ability of 17 other hydrazine derivatives to a lkylate liver DNA was determined after single administration to young adult male Sprague-Dawley rats or C57BL6 mice. Quantifiable amounts of N-7-methylguanine were measured in liver DNA from animals treated wit h 10 of the 17 compounds. In 3 of the 10 cases quantifiable amounts of O-6-methylguanine were also measured. Methylation of liver DNA guanin e was obtained with hydrazine, hydralazine, procarbazine, isoniazid, p henylhydrazine, nialamide, nitrofurazone, maleic hydrazide, sulfometho xypyridazine, and sulfamethiazole and two hydrazine-formaldehyde polym erization products, formalazine and tetraformyltrisazine. (C) 1994 Aca demic Press, Inc.