INTEGRATED CLINICAL & BASIC STUDIES OF TOXICOLOGY

减少实验结果外推的不确定度 实验室动物对人类暴露在低剂量下仍然是主要的 毒理学领域悬而未决的问题具有全球性的医学、经济、法律和 政治后果。以补充目前唯一可用的 人口流行病学研究的方法，我们的计划项目是 临床毒理学还寻求利用分子生物学的进展 和临床医学来定义遗传和环境因素， 确定对特定个人的不利健康影响的风险。 分子和细胞生物学以及分析方法已经取得了进展 足以研究人体组织或人体内的毒性机制 直接存在的生物。在即将到来的项目期，我们的目标是 重点关注细胞色素P-450(特别是III类细胞色素)和 相关酶(包括P-糖蛋白运输系统)，使 动物和人类之间的近距离比较，并提高能力 使中毒后果的风险个体化。为了实现这一点，我们修订了 计划项目正在以一种集成的方式处理这个问题 三个层次的复杂性。古泽利安博士的项目专注于分子 人第III类细胞色素P-450的分离与鉴定 基因(HLP)。监管区域和控制将被定义和人性化 Nance博士和John博士进行的双胞胎DNA多态分析 Schuetz用于确定控制表型变异的遗传位点 这些基因的表达。Erin Schuetz博士正在评估这一表达 在完整的细胞中利用新定义的系统 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 细胞色素P-450基因的细胞表达将被描述。 沃特金斯博士通过不同的方式证实了这些基本发现 对活人的侵入性研究。它是通过以下组合实现的 我们试图理解这些基因控制的这些努力是 以及它们的功能。通过使用这些技术，它可能会 有可能克服人类面临的伦理和实践障碍 实验。最后，沃特金斯博士与卡明斯基博士和 沃灵顿将评估一系列有前景的非侵入性治疗方法 对人类进行III类和其他形式的表型鉴定 细胞色素P-450。这些后续的基因分析和验证 分子和细胞分析的结果。促进……的工作 所有的项目都是细胞培养和组织库的核心 提供了这些调查所需的人力材料。通过这件事 信息从亚临床到临床水平再回到临床的循环 再说一次，对基因理解的改进是完全可以期待的 结构、基因表达和疾病结局可以通过 建议的研究计划。

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.