Mutagenic activation of CL64,855, an anti-Trypanosoma cruzi nitroderivant,by bacterial nitroreductases

CL64,855 is a nitroimidazole-thiodiazole derivate with high anti-Trypanosom a cruzi activity. CL64,855-induced mutagenesis in the Salmonella/microsome test was detected by TA98 and TA98dnp(6) strains, but not by the nitroreduc tase I-deficient TA98nr strain. The lack of mutagenic response of TA98nr wa s connected with its extreme resistance to the killing effect of the drug. Presence of S9 mix did not restore mutagenic activity of CL64,855 to the TA 98nr strain. Additionally, CL64,855 was reduced in vitro, by the nitroreduc tase I-proficient TA98 strain, mainly in the presence of oxygen, but not by the TA98nr strain. Mutagenic activity was detected in serum samples of tre ated guinea pigs by nitroreductase-proficient strains TA98 and TA98dnp(6), but not by nitroductase-deficient strain TA98nr. In the case of urine, muta genic activity was observed with all three tested strains, suggesting an in vivo metabolic activation of the drug by a distinct metabolic pathway.