Carcinogenesis Advance Access published online on December 29, 2005
Carcinogenesis, doi:10.1093/carcin/bgi303
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1 Feist-Weiller Cancer Center, Cancer Prevention and Control, Shreveport, LA
* To whom correspondence should be addressed. Naturally occurring coumarins (NOCs) are anti-carcinogenic in the mouse skin model. To characterize the chemopreventive potential of NOCs against breast cancer, we first examined their effects on 7,12-dimethylbenz[a]anthracene (DMBA)-DNA adduct formation in mouse mammary gland. We hypothesized that those NOCs that both inhibited cytochrome P450 1A1/1B1 and induced hepatic glutathione S-transferases (GSTs) would be the most effective in blocking DMBA-DNA adduct formation in mouse mammary gland. To address this hypothesis, simple coumarins (e.g., coumarin and limettin, which induced mouse hepatic GSTs but had little effect on P4501A1/1B1) and linear furanocoumarins (e.g., imperatorin and isopimpinellin, which induced hepatic GSTs and were potent inhibitors of P4501A1/1B1) were compared. Mice were pretreated with NOCs (150 mg/kg bw, by gavage) prior to either a single dose of DMBA (50 µg) or multiple doses of DMBA (20 µg daily for 3 wk and 6 wk). Mammary DMBA-DNA adduct formation was quantitated by the nuclease P1-enhanced 32P-postlabeling assay. With the single dose of DMBA, coumarin, limettin, imperatorin, and isopimpinellin, inhibited DMBA-DNA adduct formation by 50%, 41%, 79%, and 88%, respectively. Coumarin, limettin, and imperatorin blocked DMBA-DNA adduct formation by 36%, 60%, and 66% at 3 wks, and by 0%, 49%, and 55% at 6 wks of DMBA dosing, respectively. In a 6 wk dose-response study of select NOCs and 7,8-benzoflavone (a potent P4501 inhibitor that had little effect on GSTs), DMBA-DNA adduct formation was inhibited by 0%, 43%, and 24% in the limettin groups; by 26%, 26%, and 69% in the isopimpinellin groups; and by 80%, 96% and 97% in the 7,8-benzoflavone groups at 35, 70, and 150 mg/kg, respectively. Taken together, these results suggest that linear furanocoumarins had a greater inhibitory effect on DMBA-DNA adduct formation in mouse mammary glands compared to simple coumarins, and that the predominant effect may be P4501 inhibition.
Received July 28, 2005
Revised October 28, 2005
Accepted December 6, 2005
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Naturally occurring coumarins inhibit 7,12-dimethylbenz[a]anthracene DNA adduct formation in mouse mammary gland
Misty Prince 1,
Cheryl T. Campbell 2,
Taylor A. Robertson 2,
Amy J. Wells 2,
and
Heather E. Kleiner 1 *
2 Louisiana State University-Health Sciences Center, Department of Pharmacology, Toxicology & Neuroscience, Shreveport, LA
Heather E. Kleiner, E-mail: hklein{at}lsuhsc.edu
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