4.5 Article

Naturally occurring coumarins inhibit human cytochromes P450 and block benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene DNA adduct formation in MCF-7 cells

Journal

CHEMICAL RESEARCH IN TOXICOLOGY
Volume 16, Issue 3, Pages 415-422

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/tx025636d

Keywords

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Funding

  1. NCI NIH HHS [CA 16672, CA 79442] Funding Source: Medline
  2. NIEHS NIH HHS [ES07783] Funding Source: Medline

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Naturally occurring coumarins (NOCs) inhibit polycyclic aromatic hydrocarbon-induced skin tumor initiation in mice by blocking cytochrome P450 (P450)-mediated bioactivation of benzo[alpha]pyrene (B[alpha]P) and 7,12-dimethylbenz[alpha]anthracene (DMBA). Bergamottin selectively inhibits tumor initiation by B[alpha]P, whereas imperatorin and isopimpinellin inhibit tumor initiation with both carcinogens. The goals of the current study were to examine the ability of NOCs to inhibit human P450s in vitro and to establish whether NOCs, which are anticarcinogenic in mice, can block carcinogen bioactivation in cultured human cells. For the initial experiments, incubations containing 5 muM P450, P450 substrate, an NADPH generating system, and NOCs were used to determine the concentrations of each inhibitor that blocked 50% of P450 activity (IC50). These results confirmed that NOCs are capable of inhibiting multiple human P450s and that they exhibit selectivity for certain isoforms of human P450s. In subsequent experiments, we examined the effects of bergamottin, imperatorin, and isopimpinellin on DMBA and B[alpha]P DNA adduct formation in the human breast MCF-7 adenocarcinoma cell line. Coincubation of cells with the three different NOCs significantly inhibited DMBA DNA adduct formation by 29-82% at doses ranging from 2 to 10 muM and significantly inhibited B[alpha]P DNA adduct formation by 37-80% at doses ranging from 20 to 80 muM. HPLC analysis of the DNA hydrolysates demonstrated that inhibition of DNA adducts corresponded to inhibition of the major B[alpha]P and DMBA diol-epoxide-derived adducts. Although bergamottin was not effective at blocking DMBA bioactivation in the mouse skin model, it was similar in effectiveness to imperatorin and isopimpinellin in MCF-7 cells. These results demonstrate that NOCs, which are present in citrus fruits and other components of the human diet, are capable of inhibiting carcinogen metabolizing enzymes and blocking bioactivation of both B[alpha]P and DMBA in MCF-7 cells.

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