N-〔4-(5-Nitro-2-furyl)-2-thiazolyl〕formamide(FANFT)の膀胱発癌機構についての研究

Abstract

The urinary bladder carcinogenicity of N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) was investigated by feeding a diet containing 0.188% FANFT to female Fisher rats. Urinary bladder carcinoma incidences of 0% (0/5), 10% (3/30) and 16% (7/44) were observed in rats killed immediately after receiving FANFT for 10, 15 and 20 weeks respectively as compared to bladder carcinoma incidences of 0% (0/8), 50% (4/8) and 33% (9/27) for rats fed FANFT at the same dose and time period but placed on a control diet for up to 30 weeks. Severe hyperplasia of the bladder epithelium including papillomas were observed in almost all the animals fed FANFT for 15 or 20 weeks. The mutagenic activity in the urine of rats and mice administered FANFT or 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT), one of the metabolites of FANFT, was assayed with spot and plate tests for mutagenicity in Salmonella typhimurium TA100. The mutagens excreted into the urine were also analyzed by methods combining TLC and mutation tests. The data thus obtained clearly demonstrated that the mutagenicity of the urine of rats and mice administered FANFT was significantly greater than that of the animals administered ANFT, and that ANFT excreted into the urine was mainly responsible for the mutagenicity of the urine of the animals administered FANFT or ANFT. It was also demonstrated that the concentration of ANFT in the urine of rats and mice administered FANFT was more than 8 and 6 times higher respectively than that of the animals administered ANFT. Radioisotopic studies showed that the amount of ANFT excreted into the urine for 24 hours after oral administration of FANFT comprised less than 5% of all the urinary metabolites of FANFT in mice, despite the fact that ANFT excreted into the urine was mainly responsible for the strong mutagenic activity of the urine. The results were discussed and it was concluded that FANFT has a potent carcinogenicity for the urinary bladder of rats, and that ANFT excreted into the urine after administration of FANFT may be responsible for the urinary bladder carcinogenicity of this compound.