AASLD-FDA-NIH-PhRMA Hepatotoxicity Steering Group Meeting, 2006 Presentations: Role of cytokines and other factors in protecting the liver from drug-induced disease
Lance R. Pohl, Pharm.D., PhD
Section of Molecular and Cellular Toxicology,
NHLBI, National Institutes of Health
Role of cytokines and other factors in protecting the liver from drug-induced disease [PDF]
Drug-induced liver disease (DILD) is thought to be mediated by both allergic and non-allergic mechanisms of pathology. Most cases are idiosyncratic and difficult to predict due in large part to insufficient knowledge of predisposing risk factors. Recent murine model studies, however, have led to the discovery of several potential susceptibility factors that may predispose individuals to DILD. For example, we found that mice deficient in the immunoregulatory interleukins (IL)-4, IL-6, IL-10, or IL-13 are more susceptible than wild type mice to acetaminophen-induced liver injury (AILI). Other immunoregulatory processes associated with AILI led to an inhibition of the immune system that is mediated by activated Kupffer cells and lymphocytolytic processes. In addition, genomic and proteomic studies revealed that SJL mice, which are resistant to AILI, have higher levels of several potential hepatoprotective proteins than those of highly susceptible C57Bl/6 mice. These findings suggest that deficiencies in one or more regulatory pathways as a result of polymorphisms and/or environment factors may contribute to the incidence of both allergic and non-allergic DILD.
Dr. Lance Pohl is the Chief of the Molecular and Cellular Toxicology Section of the Laboratory of Molecular Immunology in the National Heart, Lung, and Blood Institute of the NIH. He received his B.A. in microbiology from the University of California, Berkeley, and Pharm.D. and Ph.D. in medicinal chemistry from the University of California Medical Center, San Francisco. Current studies deal with the role of cytokines and other regulatory factors in modulating the susceptibility of patients to drug-induced liver diseases that are mediated by reactive metabolites and cells of the innate and adaptive immune systems. Genomic, proteomic, and bioinformatic methods are used to discover the susceptibility factors and transgenic animal models are developed to elucidate the molecular and cellular activities of the factors.