Drugs and other chemicals have numerous salutary effects on humans, but they may also cause toxicity. Because of the central role played by the liver in metabolism, the liver is the most frequent and important site of drug- or chemical-induced tissue injury. As more drugs have been developed and used and more so-called complementary medicines (CAM) and herbal remedies are used, drug-induced liver disease (DILD) has become a problem of major and growing importance, and there is a growing need for better systems for early detection, characterization, and reporting of instances of DILD. Such systems should be applied both to drugs still under development and to drugs, CAM, and herbal remedies already on the market. The long-term aim of this research program is to develop a regional consortium and network in the Northeastern U.S.A. for the detection and clinico-pathological and molecular (genomic, proteomic) characterization of DILD. A key aspect of this work will be to develop a clinical, laboratory, and histopathological data base of "phenotypic" information on subjects with known or suspected DILD, and also to establish DNA, RNA, serum, and tissue banks on these same subjects. This will facilitate the development of "genotypic" (DNA), gene expression (RNA), and protein expression (proteomic) profiling of the same subjects, eventually permitting the detailed phenotypic-genotypic-proteomic correlations that will be possible as candidate genes and gene products involved in DILD are identified and characterized. Indeed, the regional and national data bases that will be established as a result of this program will aid us in discovering and identifying such genes and gene products, thereby bringing to fruition the enormous potential implicit in the successful sequencing of the human genome. The specific aims of this proposal are to: (1.) establish one of the national interactive Clinical Centers of the Hepatotoxicity Clinical Research Network, based at the University of Connecticut Health Center (UCHC). Our Center will serve as the coordinating center for a consortium of academic and practicing hepatologists and groups in the Northeastern U.S.A. We will take advantage of the strong research infrastructure of the UCHC Office of Clinical Research and the NIH-supported GCRC at UCHC; (2.) work with other members of the Network nationwide to develop consistent, standardized approaches and instruments to identify and fully characterize bona fide cases of drug-, CAM-, and toxin-induced liver injury, identified retrospectively. We will also obtain data from suitable control subjects thereby allowing for case-control studies, which will facilitate studies of the epidemiology and clinical spectrum of such hepatotoxicity; (3.) do prospective studies of selected, commonly used hepatotoxic drugs (HAART for HIV, INH for tuberculosis, methotrexate (MTX) for psoriasis); and (4.) obtain biological samples (blood, liver, plasma, serum) for study of the pathogenesis of DILD, using biochemical, serological, genetic, and proteomic techniques. The clinico-pathological database and the tissue and DNA repositories will permit us to create and test numerous hypotheses relating to the pathogenesis and pharmacogenomics of DILD.

U01DK065193

2003-09-30

2009-06-30