Activation of tinidazole, an antiprotozoal drug to a mutagen by mammalian liver S9

Abstract

Tinidazole was found to display much higher mutagenic activity compared to metronidazole in Salmonella strain TA100 and YG1029. Under anaerobiosis, the specific activity of this nitroimidazole was enhanced, at least, by about 1.75-fold in TA100 and several fold in TA100NR relative to aerobic conditions. The mutagenicity in the latter strain with S9 mix became further increased by 2.5-fold under anaerobiosis, indicating the role of oxygen sensitive bacterial and mammalian S9 nitroreductases in the activation of the drug. The mutagenicity of the drug was slightly lowered in TA100/1,8-DNP₆ (O-acetyltransferase deficient), YG1029 (O-acetyltransferase overexpressing) and TA100 in the presence of pentachlorophenol (PCP), an O-acetyltransferase inhibitor. These results rule out the possible involvement of N-acetoxyarylamine pathway in the metabolic activation of these nitroimidazoles.