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 O6-methyl- and N7-methylguanines in DNA. Incubation of calf thymus DNA with the hydrazine derivative, hydralazine, and formaldehyde resulted in the production of N7-methylguanine and two aberrant bases in DNA. These bases were separated by strong cation-exchange high-performance liquid chromatographic fractionation of neutral thermal hydrolysates. Administration of hydralazine to rats resulted in the formation of N7-methylguanine in liver DNA, but the two unknown bases observed in the in vitro experiment could not be demonstrated in vivo. In contrast to hydrazine, administration of hydralazine resulted in the methylation of DNA only at doses approaching the LD50, suggesting that formylation does not represent a significant mechanism for hydralazine toxicity in the system described. Hydralazine in combination with formaldehyde resulted in the formation of triazolophthalazine, a metabolite which has been characterized in man. The ability of 17 other hydrazine derivatives to alkylate liver DNA was determined after single administration to young adult male Sprague-Dawley rats or C57BL6 mice. Quantifiable amounts of N7-methylguanine were measured in liver DNA from animals treated with 10 of the 17 compounds. In 3 of the 10 cases quantifiable amounts of O6-methylguanine were also measured. Methylation of liver DNA guanine was obtained with hydrazine, hydralazine, procarbazine, isoniazid, phenylhydrazine, nialamide, nitrofurazone, maleic hydrazide, sulfomethoxypyridazine, and sulfamethiazole and two hydrazine-formaldehyde polymerization products, formalazine and tetraformyltrisazine.
Mathison
B H
BH
Department of Community and Environmental Medicine, University of California at Irvine 92717.
Murphy
S E
SE
Shank
R C
RC
D000478:Alkylation; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006830:Hydralazine / Q000633:toxicity*; D006834:Hydrazines / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley
D006834:Hydrazines; D005557:Formaldehyde; D006830:Hydralazine; D006147:Guanine; C008450:7-methylguanine; D004247:DNA; C008449:O-(6)-methylguanine