REGULATION OF P-450 III CYTOCHROMES IN LIVER & INTESTINE

肝脏中 P-450 III 细胞色素的调节

• 批准号: 3294251
• 负责人: PAUL B WATKINS
• 金额: $ 16.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3294251
• 关键词: biotransformation; breath tests; carbon; chlorohydrocarbon insecticide; cytochrome P450; environmental toxicology; enzyme mechanism; enzyme substrate; gel electrophoresis; gene expression; genetic regulation; genetic translation; hepatocellular carcinoma; human tissue; immunochemistry; laboratory rat; liver cells; liver metabolism; liver pharmacology; microsomes; monoclonal antibody; protein metabolism; radioimmunoassay; radionuclides; radiotracer; spectrometry; tissue /cell culture; twin /multiplet

Cytochromes P-450 belonging to the P-450III gene family are major Phase I enzymes present in the liver and intestinal mucosa of rats and man. There are large interindividual differences in the expression of P-450III cytochromes and it is likely that this explains, atleast in part, the interpatient variation in oral bioavailability that is characteristic of P-450III substrates such as cyclosporine A, nifedipine, ethinyl estradiol and erythromycin. Studies performed to date suggest that the regulation of the liver and intestinal P-450III cytochromes is qualitively different. The goal of the proposed research is to continue identification of the environmental and genetic factors which influence the catalytic activity of P-450III cytochromes in human liver and intestine by 1). assaying characteristics of these and 5 other human cytochromes P-450 in live r and in duodenal mucosal biopsies obtained from patients with known medication and medical histories 2). validating noninvasive assays of the catalytic activity of P-450III cytochromes in liver (intravenous erythromycin breath test and urinary excretion of 6 Beta hydroxy cortisol) and intestine (oral erythromycin breath test) by testing patients undergoing liver and/or intestinal biopsies 3). identifying the P-450III genes expressed in intestinal mucosa by using the polymerase chain reaction and isozyme-specific synthetic oligonucleotide primers 4). determining if the wide range of compounds known to induce P-450III cytochromes in rat liver also induce P-450III mRNA, protein, catalytic activity and rate of denovo synthesis in rat intestine and 5) culturing explants of rat and human small bowel mucosa to define a valid in vitro model for regulation studies. The data obtained from the continuing basic investigation of the P-450III cytochromes in rat and man are essential to understanding the important roles they are likely to play in health and disease.

属于P-450 III基因家族的细胞色素P-450是主要的I相 酶存在于肝脏和肠粘膜的大鼠和人。有 P-450 III的表达存在很大的个体间差异 细胞色素，这很可能解释了，至少部分， 口服生物利用度的患者间差异是以下特征 P-450 III底物，如环孢菌素A、硝苯地平、炔雌醇 和红霉素。迄今为止进行的研究表明， 肝和肠P-450 III细胞色素定性 不同.拟议研究的目标是继续 确定影响的环境和遗传因素 人肝细胞色素P-450 Ⅲ催化活性 肠1）。分析这些人和其他5个人的特征 肝和十二指肠粘膜活检中的细胞色素P-450 来自已知药物和病史的患者2）。验证 P-450 III细胞色素催化活性的非侵入性测定 肝脏（静脉内红霉素呼气试验和尿排泄6 β-羟基皮质醇）和肠（口服红霉素呼吸试验）， 测试接受肝脏和/或肠活组织检查的患者3）。 用免疫荧光法鉴定肠粘膜中表达的P-450 III基因， 聚合酶链反应和同工酶特异性合成 寡核苷酸引物4）。确定是否有大量的化合物 已知在大鼠肝脏中诱导P-450 III细胞色素也诱导P-450 III 大鼠mRNA、蛋白质、催化活性和从头合成速率 5）培养大鼠和人小肠粘膜的外植体 以定义用于调控研究的有效体外模型。数据 从对P-450 III的持续基本调查中获得的 大鼠和人的细胞色素对于理解 它们在健康和疾病中可能发挥的作用。