Mutagenicity, carcinogenicity, distribution, and nitroreduction of 4-(5-nitro-2-furyl)thiazole in the rat

Abstract

Albino noninbred weanling female Sprague-Dawley rats were fed a powdered basic grain diet (Group 1) or a basic diet supplemented with 1540 ppm of 4-(5-nitro-2-furyl)thiazole (NFT) (Group 2). Group 2 rats consumed an estimated mean NFT cumulative dose of 42 mmol/rat, exhibited significant growth retardation and hepatomegaly, and displayed 46 neoplasms (24 multiple mammary fibroadenomas, 19 forestomach squamous cell carcinomas, and 3 other malignant tumors) in 31 of 35 rats histologically evaluated. Six of 36 control rats had solitary, benign mammary fibroadenomas. After p.o. administration of NFT, extraction of urine with chloroform:diethyl ether followed by gas chromatography provided a major peak with a retention time of about 4 min. Catalytic hydrogenation of NFT with palladium on activated carbon afforded a product with the same retention time. The isolated urinary metabolite of NFT exhibited mass spectral fragmentation patterns and gas and high-pressure liquid chromatographic retention times similar to those of the chemical reduction product. These data demonstrate the identical chemical characteristics of the in vivo urinary metabolite of NFT and the compound obtained by chemical reduction of NFT. Spectroscopic analyses established the structural identity of this reduced product as 1-(4-thiazolyl)-3-cyano-1-propanone. Forty-eight hr after the intragastric administration of [14C]NFT, 32% of radioactivity was recovered in urine, 57% was recovered in gastrointestinal contents and feces, and 5.5% was recovered in expired 14CO2. About 2% of the urinary radioactivity was extracted in chloroform:diethyl ether, suggesting that 1-(4-thiazolyl)-3-cyano-1-propanone is quantitatively a minor urinary metabolite of NFT. 1-(4-Thiazolyl)-3-cyano-1-propanone was 1.1 x 10(4)-fold less active than was NFT in the Ames mutagenicity assay with Salmonella typhimurium TA 100.