Biotransformation of the Bladder Carcinogen JV-[4-(5-Nitro-2-furyl)-2- thiazolyl]formamide in Mice1

The biotransformation of A/-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT), a potent urinary bladder carcinogen, was studied in mice. About 82% of radioactivity was excreted as 14C02within 36 hr after intragastric administration of /V-[4-(5-nitro-2-furyl)-2thiazolyl]-[14C]formamide, suggesting its deformylation to 2amino-4-(5-nitro-2-furyl)thiazole (ANFT). The latter was formed in vitro as a product following incubation of FANFT with mouse liver homogenates. Chromatographie analysis of mouse urine obtained 24 hr after the i.p. administration of A/-[4-(5-nitro-2furyl)-[2-14C]thiazolyl]formamide revealed excretion of ANFT and unmetabolized FANFT, suggesting the prevalence of the defor mylation reaction in vivo. In addition, at least two more metabo lites were present in urine. One of these metabolites exhibited Chromatographie properties similar to those exhibited by a com pound derived from the in vitro nitroreduction of ANFT. This metabolite was isolated from urine of FANFT-fed animals and from in vitro enzymatic reduction of ANFT with mouse liver homogenates. The isolated products had Chromatographie and spectral properties and a mass spectral fragmentation pattern similar to that of a compound obtained by catalytic reduction of ANFT with palladium and activated carbon. Spectroscopic analyses established the structural identity of the chemical re duction product as 1-[4-(2-aminothiazolyl)]-3-cyano-1-propanone (ATCP). Since the Chromatographie properties of the enzymatically derived product and the urinary metabolite were identical to those of a compound obtained by chemical reduction, they must be structurally the same and thus correspond to ATCP. About 5% of the urinary metabolites of FANFT is ATCP, and thus ATCP is quantitatively a minor excretory product. ATCP was far less active than was ANFT or FANFT in the Ames mutagenicity assay with Salmonella typhimurium TA 100.