LOW CLASTOGENIC ACTIVITY IN-VIVO OF THE N-NITROSO DERIVATIVES OF 5 BETA-ADRENERGIC-BLOCKING DRUGS PROVED TO BE POTENT GENOTOXINS IN-VITRO

The N-nitroso derivatives formed by the in vitro reaction of 5 beta-ad renergic-blocking drugs with sodium nitrite and previously found to in duce DNA fragmentation and repair in primary cultures of both rat and human hepatocytes were tested for their ability to exert a clastogenic effect in vivo. In partially hepatectomized rats given by gavage a si ngle dose of 1000 mg/kg, all 5 N-nitroso derivatives caused a statisti cally significant increase in the frequency of micronucleated hepatocy tes, the clastogenic potencies of NO-propranolol, NO-metoprolol, and N O-nadolol being slightly greater than those of NO-atenolol and NO-sota lol. In contrast, none of them produced a significant increase in the frequency of micronucleated polychromatic erythrocytes in the bone mar row and the spleen. For all 5 N-nitroso derivatives the in vivo clasto genic potency, i.e. the ratio between the number of micronuclei observ ed in the liver and the dose administered, was markedly lower than the in vitro DNA-damaging potency calculated as the ratio between the amo unt of DNA fragmentation and the concentration tested. This suggests a preferential detoxification in vivo of the 5 N-nitroso derivatives.