Barbital sodium, a tumor promoter for kidney tubules, urinary bladder, and liver of the F344 rat, induces persistent increases in levels of DNA synthesis in renal tubules but not in urinary bladder epithelium or hepatocytes.
The nephrotoxicity of barbital sodium (NaBB), a renal and urinary bladder tumor promoter, was investigated in male F344/NCr rats. In an 8-week toxicity study, NaBB was administered to 6-week-old male rats for 8 weeks at dietary levels of 16,000, 8000, 4000, 2000, 1000, or 0 ppm. Rats tolerated NaBB at levels of 4000 ppm and below with no weight depression or mortality. Liver-to-body weight ratios, however, were significantly increased at 4000 ppm, and toxic renal lesions were observed histologically. Light microscopic studies of male rats fed 1000 ppm NaBB for 2-52 weeks or 4000 or 8000 ppm for 8 weeks revealed elevated levels of DNA synthesis in renal tubular cells as measured with tritiated thymidine autoradiography or 5-bromo-2'-deoxyuridine immunohistochemistry that were associated with degenerative and regenerative nephrotoxic lesions. Increased labeling indices of urothelium and hepatocytes were not seen in rats exposed to 1000 ppm NaBB which is effective as a bladder and liver tumor promoter at these doses. These studies provide evidence for the chronic nephrotoxicity and renal tubular hyperplasia induced by NaBB in F344 rats, which are associated with the tumor-promoting activity of NaBB at the doses studied. Hyperplasia in the urinary bladder or liver was not found, however, for this bladder and liver tumor promoter. The conflicting findings in liver, bladder, and kidney are discussed.
Hagiwara
A
A
Division of Cancer Etiology, National Cancer Institute, Frederick, Maryland.
Diwan
B A
BA
Ward
J M
JM
D000818:Animals; D001462:Barbital / Q000633:toxicity*; D001463:Barbiturates / Q000633:toxicity*; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D004247:DNA / Q000096:biosynthesis*; D004847:Epithelial Cells; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000139:chemically induced*; D007684:Kidney Tubules / Q000473:pathology; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D001743:Urinary Bladder / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced*
D001463:Barbiturates; D001462:Barbital; D004247:DNA