In vivo and in vitro genotoxicity of three antihypertensive hydrazine derivatives (hydralazine, dihydralazine, and endralazine)

Abstract

Three antihypertensive hydrazine derivatives (hydralazine, dihydralazine, and endralazine) were found to be genotoxic in four in vivo or in vitro short-term test systems. a) In mice, a single ip administration of the LD50 of the three drugs caused a small but statistically significant increase over controls in DNA elution rate, ie, a modest amount of DNA fragmentation, in three of the four organs (liver, lung, kidney, and spleen) tested, DNA damage being absent in lung for hydralazine and endralazine and in liver for dihydralazine. Only for hydralazine DNA lesions were always repaired within 12 hr, in agreement with the constant lack of cumulative effects in mice given five successive daily doses. The rank of potencies was hydralazine greater than dihydralazine greater than endralazine. b) In mice bone marrow cells, all three hydrazine derivatives induced a modest but statistically significant increase over controls in the frequency of sister chromatid exchanges, the rank of potencies being in this case dihydralazine greater than endralazine greater than hydralazine. c) In the Ames reversion test all three drugs behaved as direct-acting mutagens of low potency, whose activity was not influenced by rat liver nor by mouse liver or lung S-9 fractions. Hydralazine and dihydralazine elicited mixed genetic mechanisms of mutations, while endralazine exclusively induced frameshift errors in Salmonella DNA. The recently developed strain TA97 was the most efficient in revealing frameshift errors with all three drugs. d) The selective lethality assays in a battery of two S typhimurium and five E coli strains confirmed the direct genotoxicity of hydralazine, dihydralazine, and endralazine, in order of potency. Potency was evaluated by means of a sensitive and reliable micromethod procedure. Among those investigated, the recA recombination repair and the lexA post-replication repair ("SOS functions") and, to a lesser extent, also the polymerase I mechanism, appeared to contribute to the specific DNA repair with all three drugs, while excision repair systems (uvrA and uvrB) did not appear to be involved.

Hydralazine induces Z-DNA conformation in a polynucleotide and elicits anti(Z-DNA) antibodies in treated patients

“…Sinha and Patterson (1983) found strong binding of hydralazine to DNA and postulated intercalation of the drug between DNA bases. This drug also induced initiation of DNA repair in primary cultures of rat hepatocytes and was mutagenic in the Ames test, further suggesting drug-DNA interaction (Flora et al, 1982). Meltingtemperature measurements showed that hydralazine destabilized double-helical DNA (Eldredge et al, 1974).…”

Biotransformation of Hydrazine Dervatives in the Mechanism of Toxicity

“…However, the use of hydralazine in the clinic has been implicated in the development of severe forms of systemic lupus erythematosus in patients who have a slow acetylator-phenotype. Furthermore, hydralazine causes DNA damage, and has been reported to induce some incidence of lung tumors in mice [5, 8].…”

“…Isoniazid and iproniazid, monoamine oxidase inhibitors, are in use for the treatment of tuberculosis and, until recently, as an antidepressant, respectively [6, 7]. Hydralazine is a potent arterial vasodilator and plays an important role in the management of hypertension and congestive heart failure [8]. Hydralazine is toxic and induces DNA damage, causes severe forms of systemic lupus erythematosus and has been shown to increase the incidence of lung tumors in mice [5, 9, 10].…”

DNA Cleavage and Detection of DNA Radicals Formed from Hydralazine and Copper (II) by ESR and Immuno-Spin Trapping

“…3 Hydralazine is a potent arterial vasodilator and plays an important role in the management of hypertension and congestive heart failure. 4 Hydrazines in general are toxic, and induce a variety of toxic insults. These include liver toxicity, carcinogenicity and mutagenicity.…”

“…1, 2, 4–7 Hydralazine, the least toxic of the hydrazine derivatives, induces DNA damage, 8 causes severe forms of systemic lupus erythematosus, 9–11 and has been shown to increase the incidence of lung tumors in mice. 4–6 More recently, hydralazine has been shown to inhibit DNA Methyltransferase 1 by preventing transfer of a methyl group to DNA in several cancer silencing genes/tumor suppressor genes. 9,12 It has, therefore, become an important treatment combination in cancer therapy.…”