In vitro and in vivo testing of hydralazine genotoxicity.
Hydralazine (HDZ), a p.o. effective antihypertensive drug, was evaluated for its genotoxic effects in both rodent and human cultured cells and in the intact rat. Dose-dependent amounts of DNA fragmentation, as measured by the alkaline elution technique, and of DNA repair synthesis, as revealed by autoradiography, were produced in primary cultures of metabolically competent rat hepatocytes by subtoxic HDZ concentrations ranging from 0.32 to 1.0 mM. A similar potency in inducing DNA repair synthesis was displayed by HDZ in primary cultures of hepatocytes from four human donors. A modest reduction of both DNA fragmentation (-13%) and DNA repair (approximately -50%) was observed in hepatocytes obtained from rats pretreated with indomethacin in order to reduce prostaglandin synthetase activity. In contrast, neither in rat nor in human hepatocytes, differences in N-acetyltransferase activity resulted in meaningful changes of the same end points. V79 cells, which are essentially deficient of monooxygenases catalyzing the biotransformation of xenobiotics, were as sensitive as hepatocytes to the DNA-damaging activity 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 6-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 marrow, and the p.o. administration for 14 successive days of approximately 46 mg/kg/day increased the average diameter of liver basophilic foci initiated by diethylnitrosamine.(ABSTRACT TRUNCATED AT 250 WORDS)
Martelli
A
A
Institute of Pharmacology, University of Genoa, Italy.
Allavena
A
A
Campart
G B
GB
Canonero
R
R
Ghia
M
M
Mattioli
F
F
Mereto
E
E
Robbiano
L
L
Brambilla
G
G
D000328:Adult; D000368:Aged; D000818:Animals; D001711:Biotransformation; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D006801:Humans; D006830:Hydralazine / Q000378:metabolism / Q000633:toxicity*; D006965:Hyperplasia; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D008875:Middle Aged; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009153:Mutagens; D006830:Hydralazine