Promoting activities of butylated hydroxyanisole and butylated hydroxytoluene on 2-stage urinary bladder carcinogenesis and inhibition of gamma-glutamyl transpeptidase-positive foci development in the liver of rats.

Butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) were evaluated for possible promoting activity for urinary bladder carcinogenesis in male F344 rats initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). The rats were treated with 0.01 or 0.05% BBN in the drinking water for 4 weeks and then administered 2% BHA or 1% BHT in the diet for 32 weeks. Surviving rats were killed at the end of week 36 of the experiment. The incidences of cancer and papilloma and the average number of cancers, papillomas and papillary or nodular hyperplasias (PN hyperplasias) per 10 cm of basement membrane were significantly increased in the group receiving BHA following initiation by 0.05% BBN compared with the group given BBN only. BHT also significantly increased these lesions of the bladder, but not the average number of cancers, in rats treated with 0.05% BBN. The ability of four antioxidants, BHA, BHT, sodium L-ascorbate (ascorbate) and ethoxyquin, to promote the induction of gamma-glutamyltranspeptidase (gamma-GT)-positive foci initiated by diethylnitrosamine (DENA) in the liver of F344 rats was tested. Rats were given a single i.p. injection of 200 mg/kg body weight of DENA, and 2 weeks later the animals were exposed to 2% BHA, 1% BHT, 5% ascorbate or 1% ethoxyquin, respectively, in the diet for 6 weeks. All animals were subjected to partial hepatectomy at the end of week 3. The number of gamma-GT-positive foci in the groups fed either BHA, BHT or ethoxyquin after DENA were significantly decreased compared with the control group. These findings show that BHA and BHT are promoters for the urinary bladder carcinogenesis initiated by BBN, but that these and other antioxidants significantly inhibit the induction of gamma-GT-positive foci in the liver.