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

植物化学物质对致癌物介导的致癌物质激活途径的影响

• 批准号: 6432982
• 负责人: GRACE YEH
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6432982
• 关键词: CHO cells; MCF7 cell; P glycoprotein; benzanthracenes; benzopyrenes; cancer prevention; carcinogenesis inhibitor; chemical carcinogen; chemoprevention; cytotoxicity; drug metabolism; exocytosis; flavonoids; multidrug resistance; nutrient interaction; nutrition aspect of cancer; nutrition related tag; quercetin; toxin metabolism; verapamil

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.

大量研究表明，多种饮食成分抑制啮齿动物中化学诱导的肿瘤发生，包括DMBA诱导的乳腺肿瘤。暴露于procarcinogen的许多步骤与癌细胞的抗跨形成型的跨形成始于procarcinegen的激活对遗传毒性形式。对于芳基烃（AH），此过程由AH受体（AHR）（一种胞质转录因子）启动。已经假定了AHR的天然内源性或外源配体，但在大多数情况下仍然是未识别的。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，是MCF-7人类乳腺癌细胞中细胞色素P450 1A1的抑制剂，二秒和二秒蛋白是AHR的激动剂，并导致CYP1A1 mRNA的增加。我们进一步发现，二米素（但不是二敏）对CYP1A1活性抑制。结果是Diosmetin抑制了加合物的形成和DMBA诱导的细胞毒性，而Diosmin刺激了两个参数。类黄酮Galangin是DMBA代谢的抑制剂，也是MCF-7细胞中AHR的激动剂/拮抗剂。膳食黄酮醇，槲皮素和kaempferol是AHR的配体，其差异影响CYP1A1转录。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了CYP1A1的表达。我们检查了白藜芦醇对人肝癌细胞中CYP1A1酶活性和表达的影响，并发现白藜芦醇在人乳腺癌和肝癌细胞中以剂量依赖性的方式抑制了B [A] P和TCDD诱导的CYP1A1活性。 AHR还调节了许多II期酶的转录。饮食类黄酮的解毒机制的影响正在我们目前的研究下。