Bacterial genotoxicity of nitrosated famotidine.

Abstract

Famotidine, a histamine H2-receptor antagonist, was devoid of mutagenic activity in seven his- Salmonella typhimurium strains (TA1535, TA1537, TA1538, TA97, TA98, TA100 and TA102) and was equitoxic in repair-proficient (WP2) and repair-deficient (WP2uvrA, WP67, CM561, CM571, WP100 and CM871) Escherichia coli strains, both in the presence and in the absence of S9 mix containing liver S9 fractions from Aroclor-treated rats. However, after a short pre-incubation step with nitrite in an acidic environment, the drug increased, by a direct mechanism, the number of his+ revertants in Salmonella strains TA100, TA102 and TA97 (a decrease of mutagenicity being conversely observed in TA1535) and of trp+ revertants in E. coli strains WP2uvrA and WP67. Moreover, it enhanced the induction of non-reparable DNA damage in E. coli strains simultaneously lacking the uvrA-dependent excision repair and the lexA post-replication repair pathways. The mutagenicity of acidified nitrite-famotidine mixtures was related to doses of both precursors, with a maximum production of mutagenic derivatives in a slight molar excess of nitrite. The optimal pH of the nitrosation reaction (2.0) was intermediate between the one required for cimetidine (1.5) and ranitidine (2.5). Potency of famotidine as a precursor of mutagenic derivatives was considerably lower than the one of the other two H2 blockers. The nitrosation products of all three drugs mainly induced base-pair substitutions in Salmonella DNA, to a greater extent at sites containing G.C base pairs (strain TA100) in the case of famotidine and cimetidine, and at sites containing A.T base pairs (TA102) in the case of ranitidine.(ABSTRACT TRUNCATED AT 250 WORDS)