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

Abstract

The chemopreventive potential of 1,2-dithiole-3-thione, ethoxyquin, butylated hydroxanisole (BHA) and β-naphthoflavone (BNF) was investigated in the 7,12-dimethylbenz(a)anthracene (DMBA) rat mammary tumor model. Female Sprague-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 latency, multiplicity and incidence were not affected by BHA (2.5 or 5.0 g/kg diet), but administration of low or high doses of β-napthflavone (1.65 and 3.3 g/kg diet), or high doses of ethoxyquin (5.0 g/kg diet) or 1,2-dithiole-3-thione (0.6 g/kg diet), effectively inhibited all parameters of tumorigenesis. It is presumed that many of these agents which decrease the tumorigenicity act by altering the metabolism of the carcinogen resulting in diminished numbers of reactive ultimate carcinogens. We examined both for the induction of enzymes that might alter carcinogen metabolism as well as alterations in levels of DMBA adducts to hemoglobin. A strong correlation was observed between the effect of these agents on carcinogenesis and the induction of phase I1 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. Similarly to the results on carcinogenesis the relative efficacy of compounds in inhibiting DMBA adduct formation and DMBA induced mammary tumorigenesis was BNF > 1,2 Dithiolthione >> BHA. These results support the hypothesis that these agents work by altering metabolism of DMBA to reactive intermediates but further offer the possibility that modulation of hemoglobin adducts may serve as a surrogate marker of efficacy.