Journal Article

Naturally occurring coumarins inhibit 7,12-dimethylbenz[<i>a</i>]anthracene DNA adduct formation in mouse mammary gland

Misty Prince, Cheryl T. Campbell, Taylor A. Robertson, Amy J. Wells and Heather E. Kleiner

in Carcinogenesis

Volume 27, issue 6, pages 1204-1213
Published in print June 2006 | ISSN: 0143-3334
Published online December 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi303
Naturally occurring coumarins inhibit 7,12-dimethylbenz[a]anthracene DNA adduct formation in mouse mammary gland

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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 body wt, by gavage) prior to either a single dose of DMBA (50 µg) or multiple doses of DMBA (20 µg daily for 3 and 6 weeks). 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 weeks, and by 0, 49 and 55% at 6 weeks of DMBA dosing, respectively. In a 6 week 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 with simple coumarins, and that the predominant effect may be P4501 inhibition.

Keywords: 7,8-BF, 7,8-benzoflavone; B[a]P, benzo[a]pyrene; CDNB, 1-chloro-2,4-dinitrobenzene; DCNB, 1,2-dichloro-4-nitrobenzene; DMBA, 7,12-dimethylbenz[a]anthracene; EA, ethacrynic acid; EROD, ethoxyresorufin O-dealkylase; GST, glutathione S-transferase; NOCs, naturally occurring coumarins; NQO, NAD(P)H quinone oxidoreductase; PAH, polycyclic aromatic hydrocarbon; P450, cytochrome P450, TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin

Journal Article.  7007 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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