Formation of the N-nitroso derivatives of six beta-adrenergic-blocking agents and their genotoxic effects in rat and human hepatocytes.
Six beta-adrenergic-blocking drugs, atenolol, metoprolol, nadolol, oxprenolol, propranolol and sotalol, were found to react with sodium nitrite in HCl solution, yielding the corresponding N-nitrosamines. The genotoxic activity of the six nitrosamines was evaluated in primary cultures of both rat and human hepatocytes; DNA fragmentation was measured by the alkaline elution technique, and DNA repair synthesis by quantitative autoradiography. Positive dose-related responses were produced in cells of both species after 20 h of exposure to the following subtoxic concentrations: NO-propranolol, 0.01-0.1 mM; NO-oxprenolol, 0.03-1 mM; NO-atenolol and NO-metoprolol, 0.1-1 mM; and NO-nadolol and NO-sotalol, 0.3-3 mM. Modest but statistically significant differences between the DNA-damaging potencies for the two species were observed with NO-atenolol and NO-oxprenolol, which were both more active against rat hepatocytes, and with NO-propranolol, which was more active against human hepatocytes. At equal or higher concentrations, the six N-nitrosamines did not produce DNA fragmentation in Chinese hamster lung V79 cells; this indicates that they behave as indirectly acting compounds, which need to be transformed into reactive metabolites in order to exert a genotoxic effect.
Robbiano
L
L
Institute of Pharmacology, University of Genoa, Italy.
Martelli
A
A
Allavena
A
A
Mazzei
M
M
Gazzaniga
G M
GM
Brambilla
G
G
D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000818:Animals; D001262:Atenolol / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000166:cytology*; D008297:Male; D008790:Metoprolol / Q000378:metabolism; D009248:Nadolol / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism / Q000633:toxicity*; D015538:Nitrosation; D010096:Oxprenolol / Q000378:metabolism; D011433:Propranolol / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012977:Sodium Nitrite / Q000378:metabolism; D013015:Sotalol / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D009602:Nitrosamines; D009248:Nadolol; D001262:Atenolol; D010096:Oxprenolol; D004247:DNA; D011433:Propranolol; D013015:Sotalol; D008790:Metoprolol; D012977:Sodium Nitrite