Summation effect of uracil on the two-stage and multistage models of urinary bladder carcinogenesis in F344 rats initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine.
Uracil is known to cause reversible urolithiasis and to induce papillomatosis in the urinary bladder of F344 rats. We examined whether the marked urothelial cell proliferation caused by uracil, given in the middle of the post-initiation stages, enhances the promoting activity of a promoter in the two-stage model or the promoting and/or carcinogenic activity of a low-dose carcinogen in the multistage model of urinary bladder carcinogenesis. Rats were initiated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks, and then 2% butylated hydroxyanisole (BHA) or 0.002% N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) were given during experimental weeks 4-9 and weeks 12-20. Uracil was given during weeks 9-12 at a level of 3% of the diet. Rats in the control group were treated with BBN and uracil. Rats were killed at weeks 16 and 20. At week 16, higher occurrences of papillary or nodular (PN) hyperplasia and papilloma were observed in uracil-BHA-treated rats than in the controls. At week 20, significantly higher incidences of PN hyperplasia and papilloma were observed in both uracil-EHBN- and uracil-BHA-treated groups, and a summation effect of uracil was observed. These results indicate that uracil given in the middle of the post-initiation stage enhanced the promoting activity of the compound through marked proliferation of the bladder epithelium.
Masui
T
T
First Department of Pathology, Nagoya City University Medical School, Japan.
Shirai
T
T
Takahashi
S
S
Mutai
M
M
Fukushima
S
S
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002083:Butylated Hydroxyanisole / Q000008:administration & dosage; D002085:Butylhydroxybutylnitrosamine / Q000008:administration & dosage / Q000031:analogs & derivatives; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced*; D002455:Cell Division / Q000187:drug effects; D003043:Cocarcinogenesis; D006965:Hyperplasia; D008297:Male; D009602:Nitrosamines; D010212:Papilloma / Q000139:chemically induced; D051381:Rats; D011916:Rats, Inbred F344; D014498:Uracil / Q000633:toxicity*; D001743:Urinary Bladder / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced*
D009602:Nitrosamines; D002083:Butylated Hydroxyanisole; D002085:Butylhydroxybutylnitrosamine; C010723:N-ethyl-N-(4-hydroxybutyl)nitrosamine; D014498:Uracil