Chemoprevention of DMBA-induced mammary carcinogenesis: Relationship between induction of phase II enzymes, effects on dmba-induced hemoglobin adducts and decreases in mammary tumor multiplicity

The chemopreventive potential of 1,2-dithiole-3-thione, ethoxyquin, butylat ed hydroxanisole (BHA) and beta -naphthoflavone (BNF) was investigated in t he 7,12-dimethylbenz(a)anthracene (DMBA) rat mammary tumor model. Female Sp rague-Dawley rats received a single dose of DMBA (15 mg) at 50 days of age. Chemopreventive agents were administered via the diet, beginning one week prior to DMBA dosing and continuing until one week following DMBA. Tumor la tency, multiplicity and incidence were not affected by BHA (2.5 or 5.0 g/kg diet), but administration of low or high doses of beta -napthflavone (1.65 and 3.3 g/kg diet), or high doses of ethoxyquin (5.0 g/kg diet) or 1,2-dit hiole-3-thione (0.6 g/kg diet), effectively inhibited ail parameters of tum origenesis. It is presumed that many of these agents which decrease the tum origenicity act by altering the metabolism of the carcinogen resulting in d iminished numbers of reactive ultimate carcinogens. We examined both for th e induction of enzymes that might alter carcinogen metabolism as well as al terations in levels of DMBA adducts to hemoglobin. A strong correlation was observed between the effect of these agents on carcinogenesis and the indu ction of phase II enzymes (quinone reductase and glutathione S-transferase) and glutathione in the mammary gland. We also examined the effects of BNF; 1,2-dithiol-3-thione and BHA on formation of hemoglobin adducts by DMBA. S imilarly to the results on carcinogenesis the relative efficacy of compound s in inhibiting DMBA adduct formation and DMBA induced mammary tumorigenesi s was BNF > 1,2 Dithiolthione much greater than BHA. These results support the hypothesis that these agents work by altering metabolism of DMBA to rea ctive intermediates but further offer the possibility that modulation of he moglobin adducts may serve as a surrogate marker of efficacy.