Formation of DNA-damaging nitroso compounds by interaction of drugs with nitrite. A preliminary screening for detecting potentially hazardous drugs.
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 NaNO2 (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 less than 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.
D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D003124:Colorimetry; D006224:Cricetinae; D003412:Cricetulus; D004277:DNA, Single-Stranded; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D005260:Female; D009573:Nitrites; D009603:Nitroso Compounds / Q000032:analysis / Q000096:biosynthesis / Q000633:toxicity*; D010053:Ovary / Q000187:drug effects
D004277:DNA, Single-Stranded; D009573:Nitrites; D009603:Nitroso Compounds