Pharmacogenetics of drug and carcinogen metabolism

药物和致癌物代谢的药物遗传学

• 批准号: 7463879
• 负责人: David W Hein
• 金额: $ 32.66万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 2010-12-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463879
• 关键词: 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine; 4-biphenylamine; Acetylation; Affinity; Alleles; Aromatic Amines; Breast; CYP1A1 gene; CYP1B1 gene; Carcinogen Metabolism; Carcinogens; China; Chinese Hamster Ovary Cell; Cultured Cells; DNA; DNA Adducts; DNA Repair; DNA Repair Gene; Data; Depth; Eating; Environmental Exposure; Enzymes; Epithelial Cells; Female; Frequencies; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Health; Heterocyclic Amines; Human; Individual; Investigation; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Meat; Messenger RNA; Metabolism; Molecular Epidemiology; N-acetyltransferase 1; NADPH-Ferrihemoprotein Reductase; Pharmaceutical Preparations; Pharmacogenetics; Phase; Population; Predisposition; Proteins; Rat Strains; Rattus; Relative (related person); Role; Sampling; Single Nucleotide Polymorphism; Smoker; Tennessee; Testing; Tissue Sample; Tissues; Tobacco; Tobacco smoke; Transfection; Variant; cancer risk; carcinogenicity; chemical carcinogen; congenic; cytotoxicity; gene environment interaction; genotoxicity; heterocyclic aromatic amines; human NAT1 protein; human NAT2 protein; malignant breast neoplasm; protein expression; pyridine

DESCRIPTION (provided by applicant): Genetic susceptibility to breast cancer is determined by an interaction of genes and environment but remains poorly understood. In this revised competing renewal of our investigation into the role of pharmacogenetic polymorphisms in carcinogen metabolism on genetic predisposition to cancer, we hypothesize that aromatic amine carcinogens such as 4-aminobiphenyl (ABP) present in tobacco smoke and heterocyclic amine carcinogens such as 2-amino-3-methylimidazo [4,5-f]pyridine (IQ) present in deep-fried, well-done meats are more likely to initiate breast cancer in those individuals with rapid and/or slow acetylator N-acetyltransferase- 1 (NAT1) and - 2 (NAT2) acetylator genotypes. We hypothesize that breast cancer frequency will be higher in tobacco smokers with very slow NAT2 acetylator / rapid NAT1 acetylator genotypes, and in individuals who eat deep-fried, well-done meats and are rapid for both NAT1 and NAT2 acetylator genotypes. To test this hypothesis, we propose to determine the effect of single nucleotide polymorphisms (SNPs) in human NAT1 and NAT2 on ABP and IQ genotoxicity through stable transfection of human NAT1 or NAT2 variant alleles into Chinese hamster ovary cells transfected with human CYP1A1 or CYP1B1; determine the relative level of NAT1 and NAT2 expression in normal human mammary tissue as a function of genotype; construct and characterize rapid and slow acetylator rat strains congenic at the NAT2 locus to determine the frequency of breast tumors in female rapid and slow acetylator congenic rats administered ABP or IQ; determine quantity, stability and regulatory effects of ABP or IQ on NAT1- and NAT2-specific mRNA, protein and catalytic activity; and determine the metabolism and genotoxicity of ABP and IQ in primary mammary cell cultures derived from rapid and slow acetylator congenic rats. We also will assess the effect of NAT1 and NAT2 genotypes in breast cancer risk through participation in ongoing molecular epidemiology investigations of breast cancer in Shanghai China and in Nashville, Tennessee.

描述（由申请人提供）：对乳腺癌的遗传敏感性取决于基因和环境的相互作用，但知识渊博。在对我们对药物遗传学多态性在致癌代谢中的作用在遗传易感性癌症中的作用的调查的竞争更新，我们假设在烟草和烟草烟雾和异质氨基甲酸氨基甲基氨基甲基甲基氨基甲基甲基苯基（ABP）等芳族氨基癌（如4-氨基苯基苯基（ABP））中的作用。 - 二甲基咪唑唑[4,5-F]吡啶（IQ）（IQ）（IQ）中存在的肉肉中的肉类更有可能在那些快速和/或缓慢的乙酰乙酰基N-乙酰基转移酶-1（NAT1）的个体中启动乳腺癌（NAT1）和-2（NAT2）乙酰基基因型。我们假设在Nat2乙酰基 /快速NAT1乙酰基基因型的烟草吸烟者中，乳腺癌的频率将更高，并且在吃深炸，良好的肉类并且对Nat1和Nat2乙酰基基因型的肉类迅速且迅速的个体中。为了检验这一假设，我们建议通过稳定转染人Nat1或Nat2变体等位基因转染到中国仓鼠卵巢卵巢细胞中，用人CYP1A1或CYP1B1;确定正常人乳腺组织中Nat1和Nat2表达的相对水平随基因型的函数。构造并表征了Nat2基因座的乙酰基大鼠菌株的快速和缓慢的抗乙酰基大鼠菌株，以确定女性快速和缓慢的乙酰乙酰基过同胞大鼠乳腺肿瘤的频率；确定ABP或IQ对NAT1和NAT2特异性mRNA，蛋白质和催化活性的数量，稳定性和调节作用；并确定源自快速和缓慢的乙酰乙酰基亲生大鼠的原发性乳细胞培养物中ABP和IQ的代谢和遗传毒性。我们还将通过参与上海中国和田纳西州纳什维尔的乳腺癌的持续分子流行病学研究来评估NAT1和NAT2基因型对乳腺癌风险的影响。