The Effect of Phytochemicals on the Carcinogen Activation Pathway Mediated by th

大量研究表明，多种膳食成分抑制啮齿类动物化学诱导的肿瘤发生，包括DMBA诱导的乳腺肿瘤。从暴露于原致癌物到正常细胞转化为癌细胞之间的许多步骤始于原致癌物被激活为基因毒性形式。对于芳香烃（AH），这一过程是由AH受体（AhR）启动的，AH受体是一种细胞质转录因子。AhR的天然内源性或外源性配体已被假设，但在大多数情况下仍未确定。我们确定了几种膳食多酚化合物是AhR的天然配体。我们发现姜黄素是AhR的配体，也是MCF-7人乳腺癌细胞中细胞色素P450 1A1的抑制剂，地奥司明和地奥司明是AhR的激动剂，引起CYP1A1 mRNA的增加。我们进一步发现薯蓣皂苷，而不是薯蓣皂苷，对CYP1A1活性有抑制作用。结果表明，薯蓣皂苷抑制加合物的形成，DMBA诱导细胞毒性，而薯蓣皂苷刺激这两个参数。黄酮类高良姜是一种DMBA代谢抑制剂和MCF-7细胞AhR的激动剂/拮抗剂。膳食黄酮醇、槲皮素和山奈酚是AhR的配体，对CYP1A1转录有不同的影响。我们最近发现类固醇激素脱氢表雄酮通过转录后机制抑制CYP1A1的表达。我们检测了白藜芦醇对人肝癌细胞中CYP1A1酶活性和表达的影响，发现白藜芦醇在人乳腺癌和肝癌细胞中以剂量依赖的方式抑制B[a]P和TCDD诱导的CYP1A1活性。AhR也调节一些II期酶的转录。我们目前正在研究膳食类黄酮对解毒机制的影响。

Numerous studies have demonstrated that a variety of dietary constituents inhibit chemically induced tumorigenesis in rodents, including DMBA induced mammary tumors. The many steps between exposure to a procarcinogen and the trans-formation of a normalcell to a cancer cell begin with the activation of the procarcinogen to genotoxic forms. For the aryl hydrocarbons (AH), this process is initiated by the AH receptor (AhR), a cytosolic transcription factor. Natural endogenous or exogenous ligands of the AhR have been postulated but remain, for the most part, unidentified. We identified several dietary polyphenolic compounds are natural ligands of the AhR. We found curcumin is a ligand of the AhR and an inhibitor of cytochrome P450 1A1 in MCF-7 human breast cancer cells and Diosmin and diosmetin are agonists of the AhR and causing an increase in CYP1A1 mRNA. We further found that diosmetin, but not diosmin, was inhibitory to CYP1A1 activity. The result was that diosmetin inhibited adduct formation and DMBA induced cytotoxicity, while diosmin stimulated both parameters. The flavonoid galangin is an inhibitor of DMBA metabolism and an agonist/antagonist of the AhR in MCF-7 cells. The dietary flavonols, quercetin and kaempferol are ligands of the AhR that differentially affect CYP1A1 transcription. We recently found the steroid hormone dehydroepiandrosterone inhibits CYP1A1 expression by a post-transcriptional mechanism. We examined the effect of resveratrol on CYP1A1 enzyme activity and expression in human hepatoma cells and found resverotrol inhibited the induced CYP1A1 activity by B[a]P and TCDD in a dose-dependent manner in human breast and liver cancer cells. The AhR also regulates the transcription of a number of Phase II enzymes. The effect of detoxification mechanisms by dietary flavonoids are under our current investigation.