The effects of acetaminophen, antipyrine and phenacetin on rat urothelial cell proliferation

Abuse of combination analgesics containing phenacetin, antipyrine (phenazone) and caffeine have been associated with urinary tract tumors. Phenacetin and antipyrine have been shown to be promoters of urinary tract carcinogenesis and antipyrine is also a weak urinary tract carcinogen. Acetaminophen, the main metabolite of phenacetin, is one of the most commonly used analgesics in the USA. In the present study, the dose-related effect on the cell proliferation of the urothelium was evaluated in male Sprague-Dawley rats by autoradiography. Nine groups of twenty, 6-week old rats were treated with 0.5%, 1.0% or 1.5% of acetaminophen, antipyrine or phenacetin in the diet. A tenth group of rats received control diet without added chemicals. Ten rats from each group were killed after each of 6 and 12 weeks of feeding. There was a dose-related increase in the labeling index in the urothelium of the bladder and kidney, particularly after 6 weeks of drug administration. In particular, the 1.0% and 1.5% dose levels of antipyrine and phenacetin showed a marked proliferative effect on the urothelium. In the bladder after 6 weeks, the labeling indices were significantly increased. After 12 weeks, although numerically increased, the indices were not statistically significant. In the renal pelvic urothelium the labeling index was significantly increased in antipyrine and phenacetin treated rats at doses of 1.0% and 1.5%. After 12 weeks the majority of rats treated with 1.5% antipyrine and phenacetin had labeling indices greater than or equal to 2-fold than the control rats both in the kidney and bladder. The increased labeling indices were associated with urothelial hyperplasia, in particular after 6 weeks. In the rats treated with antipyrine there were significant degenerative changes in the urothelial cells expressed as marked vacuolization. The vacuolization is considered to be a toxic effect and the beginning of cell death. Thus cell death with regeneration may be responsible for the increased labeling index in the antipyrine groups. High doses of antipyrine were also associated with renal papillary necrosis in 50% of the rats.