This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Robbiano, L. Articles by Brambilla, G. Search for Related Content PubMed PubMed Citation Articles by Robbiano, L. Articles by Brambilla, G.

Formation of the N-Nitroso Derivatives of Six ß-Adrenergic-blocking Agents and Their Genotoxic Effects in Rat and Human Hepatocytes¹

Institutes of Pharmacology [L. R., A. M., A. A., G. B.] and Pharmaceutical Sciences [M. M.], University of Genoa, and First Surgical Division of St. Martino Hospital [G. M. G.], I-16132 Genoa, Italy

Six ß-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.

¹ This work was supported by Consiglio Nazionale delle Ricerche Special Project "Oncology" (Contract 88.00545.44) and by funds of the Public Instruction Ministry (Italy).

² To whom requests for reprints should be addressed, at Istituto di Farmacologia dell'Università, Viale Benedetto XV, 2, I-16132 - Genova, Italia.

Received 10/ 8/90. Accepted 2/19/91.

This article has been cited by other articles:

				M. Berardini, P. L. Foster, and E. L. Loechler DNA Polymerase II (polB) Is Involved in a New DNA Repair Pathway for DNA Interstrand Cross-Links in Escherichia coli J. Bacteriol., May 1, 1999; 181(9): 2878 - 2882. [Abstract] [Full Text]