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

• Published in: Cancer detection and prevention 2005, Vol.29 (4), p.338-347
• Main Authors: Malejka-Giganti, Danuta, Bennett, Kristen K., Culp, Sandra J., Beland, Frederick A., Shinozuka, Hisashi, Bliss, Robin L.
• Format: Article
• Language: English
• Subjects: 7,12-Dimethylbenz[ a]anthracene; 9,10-Dimethyl-1,2-benzanthracene - analogs & derivatives; 9,10-Dimethyl-1,2-benzanthracene - antagonists & inhibitors; Adenocarcinoma - chemically induced; Adenocarcinoma - prevention & control; Animals; beta-Naphthoflavone - administration & dosage; beta-Naphthoflavone - pharmacology; Carcinogens - antagonists & inhibitors; Cytochrome P-450 Enzyme System - drug effects; Disease Models, Animal; DNA Adducts - drug effects; Enzyme activity determination; Enzyme Induction - drug effects; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacology; Female; Glucuronosyltransferase - drug effects; Glutathione Transferase - drug effects; Liver - drug effects; Liver - enzymology; Mammary DNA adducts in vivo; Mammary gland carcinogenesis; Mammary Glands, Animal - drug effects; Mammary Neoplasms, Experimental - chemically induced; Mammary Neoplasms, Experimental - prevention & control; Nifedipine oxidation (NIFOX); Phase I/phase II enzymes; Rats; Rats, Sprague-Dawley; Suppression; β-Naphthoflavone
• ISSN: 0361-090X; 1873-443X
• DOI: 10.1016/j.cdp.2005.01.005

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.