Formation of DNA‐damaging nitroso compounds by interaction of drugs with nitrite. A preliminary screening for detecting potentially hazardous drugs

Abstract

Fifty‐seven theoretically nitrosatable widely used drugs that are commonly administered orally have been screened to determine the formation of nitroso compounds by drug‐nitrite interaction and to evaluate the genotoxicity of their nitrosation products against Chinese hamster ovary (CHO) cells, measured as DNA‐damaging potency by the alkaline elution technique. The drug (0.1 mmol) was reacted with NaNO ₂ (0.4 mmol) at pH 3–3.5 for 1 h. Nitroso compounds were present in varying yield in the nitrosation mixture of 47 drugs. Twenty‐two drugs formed direct‐acting nitroso compounds capable of producing DNA fragmentation, i.e., a statistically significant (p < 0.01) increase in the elution rate of CHO cell DNA. On a molar basis, their DNA‐damaging potency varied over a 570‐fold range, with 12 exhibiting greater potency than that of N‐nitroso‐N‐methylurea.