Evaluation of nitrofurantoin on the two stages of urinary bladder carcinogenesis in the rat

The possibility that nitrofurantoin is a complete carcinogen or is an initiator or promoter of urinary bladder carcinogenesis was evaluated in male weanling F344 rats. No increase in tumor incidence was observed in rats fed nitrofurantoin at a level of 0.187% of the diet for 2 years compared to a control group. Also, no evidence of bladder initiating activity by nitrofurantoin was observed using sodium saccharin (5% of the diet) as a promoter, and no promoting activity was observed when nitrofurantoin was fed after initiation by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (0.2% of the diet for 4 weeks). In a second experiment, nitrofurantoin (at a dose of 0.187% of the diet) was administered for 6 weeks to rats with a rapidly proliferating bladder epithelium following freeze ulceration, and then the rats were treated with 5% sodium saccharin in the diet for 98 weeks. In additional rats, labelling index following [3H]thymidine injection, determined after 12 weeks of feeding nitrofurantoin, was not increased above control levels in the urinary bladder, stomach, duodenum, or liver. Metabolism of nitrofurantoin by prostaglandin H synthase (PHS) was examined using solubilized ram seminal vesicle microsomes. The rate of nitrofurantoin metabolism by PHS was much less than that observed with benzidine, and the proportion of total metabolite bound to protein was also much less than that with benzidine. These results are consistent with previous reports describing the lack of effect of nitrofurantoin on urinary bladder carcinogenesis.