Induction of DNA synthesis by sodium phenobarbital, uracil, and sodium saccharin in urinary bladder of the F344 rat

DNA synthesis in urothelial cells was determined 2, 4, 6, 10, and 16 weeks following dietary administration of promoters of bladder tumors to weanling male F344 rats. The experimental groups were fed AIN-76A diet or this diet containing 0.15% sodium phenobarbital, 3% uracil, 5% sodium saccharin, 2% sodium bicarbonate, or a combination of 5% sodium saccharin and 2% sodium bicarbonate. Two other groups were given Wayne rodent chow alone or in combination with 5% sodium saccharin. A group of rats given a drinking water containing 0.01% N-butyl-N-(4-hydroxybutyl)nitrosamine served as a positive control. With the exception of phenobarbital which increased the labeling index but did not induce hyperplasia, all other compounds increased the labeling index and induced hyperplasia. The combination of sodium saccharin and sodium bicarbonate was more effective than either compound alone in increasing the labeling index. Sodium saccharin was equally active when incorporated in either the AIN diet or the Wayne rodent chow. The present results suggest that a fundamental mechanism of bladder tumor promotion may be due to an increased DNA synthesis which leads to an increased turnover rate of urothelial cells rather than hyperplasia. However, since sodium saccharin is a promoter when incorporated into the Wayne diet but not into the AIN diet, the ability to stimulate DNA synthesis may be an important but insufficient condition for promotion by saccharin.