Ching Yung Wang

Mutagenicity of some commercially available nitro compounds for Salmonella typhimurium

Benzoyl chloride and 53 commercially available aromatic heterocyclic and aliphatic nitro compounds were tested for mutagenicity in Salmonella typhimurium TA98 and TA100. 34 of 53 nitro compounds (64%) were mutagenic, 4 in TA100 only, 15 in TA98 only, and 15 in both strains. 13 of the heterocyclic derivatives of pyridine, indole, indazole, quinoline, and benzimidazole were mutagenic. 21 of 34 mutagenic nitro compounds were bactericidal. Nitromethane was the only aliphatic tested and was not mutagenic. Benzoyl chloride, a human carcinogen, was mutagenic for TA98.

Nitroreduction of 5-nitrofuran derivatives by rat liver xanthine oxidase and reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductase

Abstract Rat liver cytosol and microsomes catalyzed the nitroreduction of N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide (NFTA), a potent carcinogen for the mouse, rat, hamster and dog, and formed a metabolite capable of binding to protein. The cytosol nitroreductase was NADH or hypoxanthine dependent and strongly inhibited by a low concentration of allopurinol. Partial purification of the cytosol nitroreductase resulted in the parallel purification of nitroreductase and xanthine oxidase. Furthermore, NFTA, as well as 11 other nitrofurans, was reduced by purified milk xanthine oxidase. The metabolite formed was capable of binding to protein. These observations suggested that the cytosol nitroreductase activity was due to xanthine oxidase. The microsomal nitroreductase, which is NADPH dependent, was probably NADPH-cytochrome c reductase. Microsomal nitroreductase activity paralleled NADPH-cytochrome c reductase activity in rats pretreated with allylisopropylacetamide (AIA), phenobarbital or 3-methylcholanthrene (3-MC), but did not parallel the level of microsomal cytochrome P-450. A partial purification of the microsomal nitroreductase resulted in the parallel purification of nitroreductase and NADPH-cytochrome c reductase. The NFTA metabolite formed by the partially purified enzyme was capable of binding to protein. Other nitrofurans also were reduced by the same enzyme preparation. Hence, microsomal nitroreductase activity may be due to NADPH-cytochrome c reductase.

Nitroreduction of carcinogenic 5-nitrothiophenes by rat tissues☆

Abstract Nitroreduction of anthelmintic and carcinogenic 5-nitrothiophenes, 4-(2,3-dihydroxypropyl-amino)-2-(5-nitro-2-thienyl) quinazoline and 4-(2-hydroxyethylamino)-2-(5-nitro-2-thienyl)quinazoline, by rat tissues was studied. A procedure for photometric determination of 5-nitro- and 5-aminothiophenes was described. Nitroreduction of 5-nitrothiophenes was catalyzed by rat liver cytosol and microsomes. Cytosol enzyme activity was hypoxanthine-dependent and inhibited by air and allopurinol. Microsomal enzyme activity was NADPH-dependent and inhibited by air. The reaction was also catalyzed by a purified milk xanthine oxidase. Since 5-nitrofurans and 5-nitrothiophenes have great similarity in structure and chemical properties, their nitroreduction may be catalyzed by the same enzymes, namely xanthine oxidase and NADPH-cytochrome c reductase. Nitroreductase activities of rat small intestine and liver were higher than those of kidney and stomach, suggesting that the small intestine and liver were the main organs for metabolism of 5-nitrothiophenes. Depending upon the source of enzyme, only 25–50 per cent of the reduced 5-nitrothiophene was converted to the corresponding amine. The rest of the reduced product may exist as reduced intermediates or bind to protein. Nitroreduction of several 5-nitrofurans was also measured.

Tumor production in germ-free rats fed 5-nitrofurans

Weanling female germ-free Sprague-Dawley rats were divided into 3 groups: the control group rats were fed an autoclaved 5010C diet for 2 years; the nitrofurantoin (NF) group rats were fed this diet supplemented with 0.188% NF for 2 years; and the N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT) group rats were fed this diet supplemented with 0.188% FANFT for 20 weeks followed by 20 additional weeks of the control diet. The FANFT-group rats were killed following the early appearance of bladder tumors. Six of 11 control rats had tumors: 2 with mammary fibroadenomas, 1 with adrenal adenoma, 1 with leukemic spleen, and 2 with mesenchymal sarcoma of the colon. Ten of 12 NF-group rats had tumors: 9 with mammary fibroadenomas, 1 with adrenal adenoma, and 1 each with leukemic spleen and cervical squamous cell carcinoma. Eight of 12 FANFT-group rats had tumors: 7 with bladder and 1 with renal pelvis transitional cell carcinoma. The incidences of mammary fibroadenoma in the NF group and of lower urinary tract tumors in the FANFT group were significantly greater (P less than 0.01) than those of these tumors in the control group.

Deacylation of carcinogenic 5-nitrofuran derivatives by mammalian tissues

Abstract The deacylations of N -[4-(5-nitro-2-furyl)-2-thiazolyl] fonnamide (FANFT), N -[4-(5-nitro-2-furyl)-2-thiazolyl] acetarnide (NFTA) and formic acid 2-[4-(5-nitro-2-furyl)-2-thiazolyl] hydrazide (FNT) by liver, kidney, small intestines and stomach of mouse, rat, hamster and guinea pig were investigated. FANFT was deformylated to 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT). FANFT formamidase activity was higher in the liver and small intestines of mouse, hamster and guinea pig, and small intestines and stomach of rat. There was no detectable FANFT formamidase activity in the stomach of the mouse and hamster. Neither NFTA nor FNT was deacylated by the rodent tissue homogenates studied. It is suggested that (1) 4 ANFT is a metabolite of FANFT but not NFTA; (2) 2-hydrazino-4-(5-nitro-2-furyl)thiazole (HNFT) may not be a metabolite of FNT; and (3) the induction of tumors by FANFT, NFTA and FNT may not be due to a common carcinogenic metabolite, although these chemicals demonstrate similar organ specificities in some of these rodents.

Mutagenicity of urine of various species fed N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide or 2-amino-4-(5-nitro-2-furyl)thiazole☆

Rats, mice and hamsters, which are susceptible to the bladder carcinogenesis by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT), and guinea pigs, which are not, were fed a diet containing 0.188% FANFT or 0.188% 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) for 1 week and their urine was then examined for mutagenicity for S. typhimurium TA100. The mutagenicities of the urine of these species fed FANFT were approximately equal. Similarly, that of the urine of these species fed ANFT were also approximately equal. However, the urine from FANFT-fed animals was approximately 10 times as mutagenic as that from ANFT-fed animals. ANFT was detected only in the urine of rats, mice or hamsters fed FANFT. A positive correlation between the susceptibility toward bladder carcinogenesis by FANFT and urinary ANFT excretion was demonstrated, although the correlation between this susceptibility and urine mutagenicity was lacking.

Production of urinary tract tumors by co-administration of uracil and N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide in F344 rats

Co-administration of uracil and N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) to weanling female Fischer rats produced uracil stones in the bladder and significantly reduced the incidence of bladder tumors. Contrary to bladder tumors, the incidence of renal pelvic and ureteric tumors was increased by this regimen. Feeding of uracil alone produced bladder tumors, in addition to the hyperplasia of renal pelvis, ureter and bladder. The mechanism of uracils effect on FANFT carcinogenesis is not known.

Enhancement by phenothiazine and 2,5-di-O-acetyl-d-glucosaccharo-(1,4)(6,3)-dilactone of bladder carcinogenicity of N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide in rats

Rats concomitantly fed N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) and phenothiazine, or concomitantly fed FANFT and Glucaron then fed Glucaron alone had significantly greater incidences of transitional cell carcinomas of the bladder than rats fed FANFT alone. Caffeine and cysteamine did not affect FANFT bladder carcinogenesis. Phenothiazine induced nitroreductase activity of hepatic microsomes.