INTEGRATED CLINICAL & BASIC STUDIES OF TOXICOLOGY

综合临床

• 批准号: 2153616
• 负责人: PHILIP S GUZELIAN
• 金额: $ 73.47万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1997-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2153616
• 关键词: cytochrome P450; detoxification; environmental toxicology

Reducing uncertainties in extrapolation of results from experiments in laboratory animals to human beings exposed to low doses remains a major unsolved problem in toxicology having global medical, economic, legal, and political consequences. To supplement the only currently available approach of epidemiological studies of populations, our program project in Clinical Toxicology seeks also to utilize advances in molecular biology and clinical medicine to define the genetic and environmental factors that determine the risks for an adverse health effect to a given individual. Molecular and cellular biology as well as analytic methods have advanced sufficiently to study mechanisms of toxicity in human tissues or in human beings directly. For the forthcoming project period our goals are to focus on the cytochromes P-450 (especially the Class III cytochromes) and related enzymes (including the P-glycoprotein transport system), make proximate comparisons between animals and humans, and advance the ability to individualize risk for toxic outcomes. To accomplish this, our revised program project is approaching the problem in an integrated fashion on three levels of complexity. Dr. Guzelian's project focuses on molecular isolation and characterization of the human Class III cytochrome P-450 genes (HLp). Regulatory regions and controls will be defined and human twin analysis for DNA polymorphisms carried out by Drs. Nance and Dr. John Schuetz to identify genetic loci controlling variation in phenotypic expression of these genes. Dr. Erin Schuetz is evaluating the expression of these genes in the intact cell utilizing newly defined systems of cultured human hepatocytes. Drugs, environmental chemicals, endocrine controls and other factors that affect the regulation of the endogenous cellular expression of the cytochrome P-450 genes will be characterized. Dr. Watkins provides confirmation of these basic findings through non- invasive studies of living human beings. It is through a combination of these efforts that we seek to understand the control of these genes as well as their functions. Through the use of these technologies, it may be possible to overcome the ethical and practical impediments to human experimentation. Finally, Dr. Watkins, working with Drs. Kaminsky and Watlington, will evaluate a series of promising noninvasive means of phenotyping humans for expression of Class III and other forms of cytochrome P-450. These subsequent gene analysis and for authenticating the results of molecular and cellular analyses. Facilitating the work of all of the projects is the Cell Culture and Tissue Bank Core which provides the human material needed for these investigations. Through this cycling of information from the subclinical to the clinical level and back again, it is fully expected that refinements in understanding gene structure, gene expression, and disease outcome can be achieved by the proposed research program.

减少实验结果外推的不确定性 实验室动物对暴露于低剂量的人类的影响仍然是一个主要的问题。 毒理学中尚未解决的问题具有全球医学，经济，法律的， 政治后果。 以补充目前仅有的 人口流行病学研究的方法，我们的计划项目， 临床毒理学还寻求利用分子生物学的进展 和临床医学来确定遗传和环境因素， 确定对特定个体产生不利健康影响的风险。 分子和细胞生物学以及分析方法取得了进步 足以研究人体组织或人体中的毒性机制 生物直接。 在即将到来的项目期间，我们的目标是 关注细胞色素P-450（尤其是III类细胞色素）， 相关酶（包括P-糖蛋白转运系统），使 动物和人类之间的近似比较，并提高能力， 个体化毒性结果的风险。 为了实现这一目标，我们的修订版 一个项目正在以一种综合的方式处理这个问题， 复杂性的三个层次。 Guzelian博士的项目集中在分子水平上， 人III类细胞色素P-450的分离和鉴定 基因（HLp）。 监管区域和控制将被定义， 南希博士和约翰博士进行的DNA多态性双胞胎分析 Schuetz鉴定控制表型变异的遗传位点 这些基因的表达。 艾琳·舒茨博士正在评估 这些基因在完整的细胞利用新定义的系统， 培养的人肝细胞。 药物、环境化学品、内分泌 控制和其他影响内源性调节的因素 将表征细胞色素P-450基因的细胞表达。 沃特金斯博士通过非- 对活人的侵入性研究 它是通过以下几个方面的结合 这些努力，我们试图了解这些基因的控制， 以及它们的功能。 通过使用这些技术， 有可能克服道德和实际障碍， 实验 最后，沃特金斯博士与卡明斯基博士合作， Watlington，将评估一系列有前途的非侵入性方法， 对人类进行III类和其他形式的 细胞色素P-450 这些随后的基因分析和鉴定 分子和细胞分析的结果。 促进委员会的工作 所有的项目都是细胞培养和组织库核心， 提供了这些调查所需的人类材料。 通过这个 信息从亚临床水平循环到临床水平，再循环回来 再次，完全可以预期，对基因的理解的改进 结构、基因表达和疾病结果可以通过 提出的研究方案。