nefurthiazole and Kidney-Neoplasms

Formic acid 2-[4-(5-nitro-2-furyl)-2-thiazolyl]-hydrazide (FNT) is a renal carcinogen in the rat. The peroxidative activity of prostaglandin H synthase oxidizes FNT into a reactive intermediate which forms 5-(S)-substituted thioether conjugates with glutathione and N-acetylcysteine. These conjugates are also formed during horseradish peroxidase oxidation of FNT. The conjugate was identified by the combined results of comparative u.v./vis. spectrophotometry, chromatographically-assisted hydrodynamic voltammetry and proton n.m.r. spectroscopy. The relative rate of PHS metabolism of FNT was similar to that observed with benzidine and 5-fold faster than ANFT, its 5-nitrofuro-2-aminothiazole analogue. These results indicate that the pathogenic effects of FNT may be caused by its peroxidative activation and that cellular thiols may attenuate the toxic effects of FNT by conjugate formation.

Topics: Acetylcysteine; Carcinogens; Glutathione; Kidney Neoplasms; Magnetic Resonance Spectroscopy; Nitrofurans; Peroxidases; Peroxides; Prostaglandin-Endoperoxide Synthases

Factors enhancing renal carcinogenesis induced by formic acid 2-[4-(5-nitro-2-furyl)-2-thiazolyl] hydrazide (FNT) were studied. Five groups of rats were used. Groups 1 and 2 were subjected to right nephrectomy and 2 days late they were injected with 20 mg/kg body weight of dimethylnitrosamine (DMN). From one week after nephrectomy, group 1 was fed on 0.2% FNT diet continuously to the end of the experiment, and group 2 was given normal diet. In week 2, they were given 400 mg/kg body weight of chloroform (CHCl3) orally. Groups 3 and 4 were given ChCl3 first and 2 days later injected with DMN. Group 3 was then fed FNT diet and group 4 was fed basal diet continuously. In week 2, groups 3 and 4 were subjected to unilateral nephrectomy. Group 5 was given FNT diet without other treatment. The incidences of tubular hyperplasia in groups 1, 3 and 5 were 53.3%, 52.9%, and 0%, respectively, at week 16 and 100%, 94.9% and 94.1%, respectively, at week 32. Moreover, the incidences of renal cell tumors in these groups were 85.0%, 88.9% and 17.6%, respectively, at week 32. Thus, the inductions of tubular hyperplasia and renal cell tumor were markedly enhanced by combined treatment with CHCl3, DMN, unilateral nephrectomy and FNT in the initiating and promoting stages.

Topics: Animals; Body Weight; Carcinogens; Chloroform; Dimethylnitrosamine; Kidney Neoplasms; Male; Neoplasms, Experimental; Nephrectomy; Nitrofurans; Organ Size; Rats; Rats, Inbred F344; Thiazoles