Mechanistic role of P4501 enzymes in the prevention of PAH carcinogenesis by omega 3 fatty acids

P4501 酶在 omega 3 脂肪酸预防 PAH 致癌中的机制作用

基本信息

批准号：
10404072
负责人：
BHAGAVATULA MOORTHY
金额：
$ 44.89万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10404072
关键词：
A/J Mouse Animal Experiments Apoptosis Aromatic Polycyclic Hydrocarbons Attenuated Benzo(a)pyrene Benzoic Acids CYP1A1 gene CYP1B1 gene Carcinogenesis Mechanism Carcinogens Cell Cycle Regulation Charcoal Clinical Trials Corn Oil Coxibs Cytochrome P450 Cytochromes DNA DNA Adduction DNA Adducts DNA Damage DNA Methylation DNA Modification Methylases DNA Repair DNA Sequence Alteration DNMT3a Development Diesel Exhaust Diet Dietary Intervention Dietary intake Disease Docosahexaenoic Acids Docosahexaenoic acid supplement EZH2 gene Eicosapentaenoic Acid Eicosatetraenoic Acids Enzymes Epigenetic Process Epoxide hydrolase Exposure to Fatty acid glycerol esters Gene Proteins Genes Goals Hepatic Human Incidence Inhalation Knockout Mice Laboratories Lead Linear Regressions Link Lung Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolism Mus Mutation Neoplasm Metastasis Omega-3 Fatty Acids Omega-6 Fatty Acids Phase Play Prevention Protein Array Proteins RUNX3 gene Repression Research Role Serum Testing Time Tissues Transgenic Organisms Tumor Suppressor Genes angiogenesis attenuation benzenesulfonamide cancer prevention cancer risk carcinogenesis cigarette smoke dietary dietary carcinogenesis docosapentaenoic acid drinking water drug metabolism environmental chemical experimental study exposed human population in vivo inhibitor lung cancer prevention novel novel strategies promoter transcriptome sequencing tumor tumor growth tumorigenesis

项目摘要

PROJECT SUMMARY The cytochrome P450s (CYPs) are the major enzymes involved in drug metabolism and bioactivation. It is well known that several CYP enzymes metabolize omega-3 fatty acids to their epoxy metabolites that inhibit angiogenesis, tumor growth, and metastasis. Numerous polycyclic aromatic hydrocarbons (PAH) are human carcinogens. PAH-DNA adducts may lead to DNA damage and mutations in critical genes, eventually leading to cancer. A significant positive linear regression between levels of PAH-DNA adducts and tumor incidence was observed in animal experiments in our laboratory. We also discovered that omega-3 fatty acids eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) inhibited CYP1B1, EZH2, DNMT3a, miR 17, miR19b-1 and significantly decreased pulmonary and hepatic PAH-DNA adducts, and tumor incidence. The central hypothesis of this application is that omega 3-fatty acids and their epoxy metabolites will attenuate pulmonary carcinogenesis by multiple mechanisms entailing attenuation of PAH-DNA adduct formation by modulating CYPs, as well as by suppression of tumorigenesis, probably via modulation of epigenetic genes (e.g., EZH2, DNMT3a, miR-17, miR-19b-1). We propose the following Specific Aims. Aim 1: To test the hypothesis that CYP1A1 and CYP1B1 play mechanistic roles in prevention of PAH carcinogenesis in mice maintained on EPA, DHA, or EPA + DHA diets, compared to those on a CO diet, followed by exposure of these mice to BP for the study of the mechanisms. Aim 2: To test the hypothesis that mice deficient in soluble epoxide hydrolase (sEH) will confer more protection than WT mice to EPA/DHA-mediated prevention of PAH carcinogenesis, as sEH is known to rapidly hydrolyze epoxy metabolites such as 17,18-epoxy eicosatetraenoic acid (EEQ) and 19,20-epoxy docosapentaenoic acids (EDP) in serum and tissues to inactive metabolites. In some experiments, we will treat WT mice with the specific sEH inhibitor, t-TUCB, or a new t-TUCB-like inhibitor (that is likely to go to human clinical trials soon), followed by treatment of mice with EPA/DHA and BP. Aim 3: To test the hypothesis that endogenous omega-3 fatty acids, especially their epoxy metabolites, will play a pivotal role in the prevention of pulmonary carcinogenesis by PAHs in vivo, and that there is a mechanistic link between CYP1, and sEH. Fat-1-transgenic (Fat-1-Tg) mice, which will convert endogenous omega-6 fatty acids (rich in CO) into omega-3 fatty acids and decrease the ratios of omega-6/omega-3, will be used in this study. We will also create Fat-1-Tg/sEH-null mice for exploring the mechanisms by which CYP1 and sEH enzymes contribute to omega-3 fatty acid-mediated prevention of PAH carcinogenesis. If our hypothesis that CYP1 and sEH enzymes play important roles in omega-3 fatty acids, i.e. EPA/DHA-mediated prevention of PAH-induced cancers turns out to be correct, then it will break new grounds in the current understanding of human cancer prevention. If successful, the proposed studies should lead to novel mechanisms in dietary interventions against lung cancers induced by PAHs.

项目摘要细胞色素P450（CYP）是参与药物代谢和生物活化的主要酶。很好知道几种CYP酶将omega-3脂肪酸代谢为抑制的环氧代谢产物血管生成，肿瘤生长和转移。许多多环芳烃（PAH）是人类致癌物。 PAH-DNA加合物可能导致临界基因的DNA损伤和突变，最终导致癌症。 PAH-DNA加合物水平与肿瘤发生率之间的显着正线性回归在我们实验室的动物实验中观察到。我们还发现omega-3脂肪酸 eicosapentaenoic（EPA），二十六烯酸（DHA）抑制CYP1B1，EZH2，DNMT3A，mir 17，17，mir 17， miR19b-1，显着降低了肺和肝PAH-DNA加合物以及肿瘤的发生率。这该应用的中心假设是欧米茄3脂肪酸及其环氧代谢物将减弱通过多种机制进行肺癌发生，需要通过调节CYP以及通过抑制肿瘤发生，可能通过调节表观遗传基因（例如EZH2，DNMT3A，mir-17，mir-19b-1）。我们提出以下特定目标。目标1：测试 CYP1A1和CYP1B1在预防PAH癌发生中起着机械作用的假设与CO饮食相比，在EPA，DHA或EPA + DHA饮食上保持这些小鼠到BP进行研究。目标2：测试小鼠可溶性缺乏的假设与WT小鼠相比，环氧化物水解酶（SEH）将对EPA/DHA介导的PAH预防的保护更多癌变，因为已知SEH可以快速水解环氧代谢物，例如17,18-环氧eicosatetraenoic 在血清和组织中，酸（EEQ）和19,20-氧基二十二烯酸（EDP）与非活性代谢产物中的酸（EDP）。在一些实验，我们将使用特定的SEH抑制剂，T-TUCB或新的T-TUCB样抑制剂治疗WT小鼠（这很可能很快就会进行人类临床试验），然后用EPA/DHA和BP治疗小鼠。目标3：为了测试内源性omega-3脂肪酸，尤其是其环氧代谢产物的假设，将发挥作用 PAHS在体内预防肺癌发生中的关键作用，并且存在机械链接在CYP1和SEH之间。脂肪-1-转基因（FAT-1-TG）小鼠，将转换内源性omega-6脂肪将酸（富含CO）成omega-3脂肪酸并降低omega-6/Omega-3的比率学习。我们还将创建FAT-1-TG/SEH无效小鼠，以探索CYP1和SEH的机制酶有助于omega-3脂肪酸介导的PAH癌变的预防。如果我们的假设是 CYP1和SEH酶在omega-3脂肪酸中起重要作用，即EPA/DHA介导的预防事实证明，PAH引起的癌症是正确的，那么它将在当前对预防人类癌症。如果成功，拟议的研究应导致饮食中的新机制针对PAH诱导的肺癌的干预措施。