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.

许多研究表明，多种膳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。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开始是原致癌物活化为遗传毒性形式。对于芳烃（AH），这一过程由AH受体（AhR）（一种胞质转录因子）启动。天然内源性或外源性配体的AhR已被假定，但仍然，在大多数情况下，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MCF-7人乳腺癌细胞中AhR的配体和细胞色素P450 1A 1的抑制剂，地奥司明和地奥司汀是AhR的激动剂，并引起CYP 1A 1 mRNA的增加。我们进一步发现，地奥司汀，而不是地奥司明，是抑制CYP 1A 1活性。结果表明，地奥司汀抑制加合物的形成和DMBA诱导的细胞毒性，而地奥司明刺激这两个参数。类黄酮高良姜素是MCF-7细胞中DMBA代谢的抑制剂和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，其差异性地影响CYP 1A 1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CYP 1A 1表达。我们研究了白藜芦醇对人肝癌细胞中CYP 1A 1酶活性和表达的影响，发现白藜芦醇以剂量依赖的方式抑制B[a]P和TCDD诱导的人乳腺癌和肝癌细胞中CYP 1A 1活性。AhR还调节许多II相酶的转录。黄酮类化合物的解毒作用机制目前正在研究中。