The phenolic food
antioxidant butylated hydroxytoluene (
BHT) has been reported to inhibit the initiation stage of 7,12-dimethylbenz[a]
anthracene (DMBA)-induced mammary
tumorigenesis in the female rat. However, the mechanism for this antitumorigenic effect of
BHT is unknown. The present studies were conducted to evaluate the relative effect of the parent chemical
BHT and two of its major oxidative metabolites,
2,6-di-tert-butyl-4-hydroxymethylphenol (
BHT-BzOH) and 2,6-di-tert-butyl-1,4-benzoquinone (
BHT-quinone), on DMBA-induced rat mammary
tumorigenesis and on the formation of rat mammary DMBA-
DNA adducts in vivo. The ip administration of either
BHT or
BHT-quinone at 200 mg/kg
body weight for 2 wk before until 1 wk after DMBA administration inhibited the development of mammary tumours as compared with controls. The extent of tumour inhibition by
BHT (39%) was greater than that exhibited by
BHT-quinone (25%). The administration of
BHT-BzOH at 200 mg/kg
body weight did not inhibit mammary
tumorigenesis. Thus, the inhibition of DMBA-induced mammary
tumorigenesis by
BHT does not appear to be mediated by the oxidative
BHT metabolites
BHT-BzOH or
BHT-quinone. In addition, there was a good quantitative correlation between the inhibition of mammary
tumorigenesis by
BHT and
BHT-quinone and their respective abilities to decrease total binding in vivo of DMBA to mammary
DNA. The inhibition of specific mammary DMBA-
DNA adducts by
BHT was not identical to the inhibition of adducts by
BHT-quinone. However, the decrease in formation of the major mammary adduct derived from the anti-dihydrodiolepoxide of DMBA bound to deoxy-
guanosine most closely correlated to the relative abilities of
BHT and
BHT-quinone to inhibit mammary
tumorigenesis. When mammary adduct formation was examined in response to
BHT dose, the administration of
BHT at doses of 100 mg/kg
body weight and 200 mg/kg
body weight resulted in the inhibition of anti-derived but not syn-derived mammary DMBA-
DNA adducts. Together, these studies suggest that in addition to the inhibition of total mammary
DMBA-DNA adduct formation, the inhibition of mammary
DNA adducts formed from the anti-dihydrodiolepoxide of DMBA also may be specifically important in the inhibitory effect of
BHT on DMBA-induced mammary
tumorigenesis.