Suppression of 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis by pre-initiation treatment of rats with beta-naphthoflavone coincides with decreased levels of the carcinogen-derived DNA adducts in the mammary gland.
BACKGROUND
Mechanisms underlying prevention by beta-naphthoflavone (beta-NF) of mammary carcinogenesis initiated with 7,12-dimethylbenz[a]anthracene (DMBA) in the rat were elucidated.


RESULTS
Treatment of female Sprague-Dawley rats with beta-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 beta-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 beta-NF, DMBA, or beta-NF followed by DMBA as in the first bioassay. Treatment with either beta-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 beta-NF. In the liver, the increase of UDP-glucuronosyl transferase (GT) activity in rats treated with beta-NF and DMBA was 2.3-fold greater than in rats treated with DMBA alone. Thus, treatment with beta-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 beta-NF-pretreated rats.


CONCLUSIONS
The beta-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.
Malejka-Giganti
Danuta
D
Veterans Affairs Medical Center, Minneapolis, MN 55417, USA. malej001@umn.edu
Bennett
Kristen K
KK
Culp
Sandra J
SJ
Beland
Frederick A
FA
Shinozuka
Hisashi
H
Bliss
Robin L
RL
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors*; D000230:Adenocarcinoma / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D002273:Carcinogens / Q000037:antagonists & inhibitors*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D018736:DNA Adducts / Q000187:drug effects*; D004195:Disease Models, Animal; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D014453:Glucuronosyltransferase / Q000187:drug effects; D005982:Glutathione Transferase / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008321:Mammary Glands, Animal / Q000187:drug effects*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019324:beta-Naphthoflavone / Q000008:administration & dosage / Q000494:pharmacology*
C059444:7,12-dimethylbenz(a)anthracene-DNA adduct; D002273:Carcinogens; D018736:DNA Adducts; D004791:Enzyme Inhibitors; D015127:9,10-Dimethyl-1,2-benzanthracene; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase