Suppression of 7,12-dimethylbenz[ a]anthracene-induced mammary carcinogenesis by pre-initiation treatment of rats with β-naphthoflavone coincides with decreased levels of the carcinogen-derived DNA adducts in the mammary gland

Abstract

Background: Mechanisms underlying prevention by β-naphthoflavone (β-NF) of mammary carcinogenesis initiated with 7,12-dimethylbenz[ a]anthracene (DMBA) in the rat were elucidated. Methods and results: Treatment of female Sprague–Dawley rats with β-NF at 40 mg/kg b.wt. for 4 days by oral gavage in corn oil before a single oral dose of DMBA (112 mg/kg b.wt.) suppressed mammary gland carcinogenesis as shown by an increase in the median latent period from 10 to 24 weeks and a 60% decrease in the multiplicity of mammary adenocarcinomas. In contrast, a 20-day treatment with β-NF starting 3 weeks after DMBA had no significant effects on mammary tumorigenesis. The activities of phase I and phase II enzymes were examined in the liver and mammary gland 24 h after treatment of rats with β-NF, DMBA, or β-NF followed by DMBA as in the first bioassay. Treatment with either β-NF or DMBA increased the hepatic activities of cytochrome P450 (CYP)1A1, 1A2, and 2B1/2, and glutathione S-transferase, and the mammary activity of CYP1A1. The activity of mammary CYP2B1/2 induced by DMBA was decreased by β-NF. In the liver, the increase of UDP-glucuronosyl transferase (GT) activity in rats treated with β-NF and DMBA was 2.3-fold greater than in rats treated with DMBA alone. Thus, treatment with β-NF likely increased the rate of glucuronidation of DMBA dihydrodiols leading to carcinogen detoxification. The levels of the DMBA adducts determined by 32P-postlabeling of the mammary gland DNA were decreased in the β-NF-pretreated rats. Conclusion: The β-NF-induced increase in the hepatic UDP-GT activity and decrease in the mammary DNA-DMBA adducts occurred under the same treatment regimen that led to suppression of DMBA-induced mammary carcinogenesis.