INTEGRATED CLINICAL & BASIC STUDIES OF HUMAN TOXICOLOGY

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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.