IN-VITRO AND IN-VIVO TESTING OF HYDRALAZINE GENOTOXICITY

Hydralazine (HDZ), a p.o. effective antihypertensive drug, was evaluat ed for its genotoxic effects in both rodent and human cultured cells a nd in the intact rat. Dose-dependent amounts of DNA fragmentation, as measured by the alkaline elution technique, and of DNA repair synthesi s, as revealed by autoradiography, were produced in primary cultures o f metabolically competent rat hepatocytes by subtoxic HDZ concentratio ns ranging from 0.32 to 1.0 mM. A similar potency in inducing DNA repa ir synthesis was displayed by HDZ in primary cultures of hepatocytes f rom four human donors. A modest reduction of both DNA fragmentation (- 13%) and DNA repair (similar to-50%) was observed in hepatocytes obtai ned from rats pretreated with indomethacin in order to reduce prostagl andin synthetase activity. In contrast, neither in rat nor in human he patocytes, differences in N-acetyltransferase activity resulted in mea ningful changes of the same end points. V79 cells, which are essential ly deficient of monooxygenases catalyzing the biotransformation of xen obiotics, were as sensitive as hepatocytes to the DNA-damaging activit y of HDZ. Moreover, after exposure to 0.1 to 0.3 mM HDZ, a modest (2.1 - to 2.8-fold), but significant, increase in the frequency of mutation to g-thioguanine resistance was observed in V79 cells in the absence of a metabolic activation system. In rats, a single p.o, dose of 80 mg /kg produced a clastogenic effect in the liver, but not in the bone ma rrow, and the p.o. administration for 14 successive days of approximat ely 46 mg/kg/day increased the average diameter of liver basophilic fo ci initiated by diethylnitrosamine. Taken as a whole, our results furt her support the hypothesis that HDZ is activated to short-lived reacti ve species by multiple mechanisms, and that the liver might be, becaus e of pharmacokinetic reasons, the main target of HDZ genotoxicity.