Molecular and Cellulary Toxicology

Lance R Pohl, PharmD, PhD, Principal Investigator

Our research focuses on the molecular and cellular basis of drug-induced liver disease (DILD). This disease is a major cause of life-threatening acute liver failure and is a key reason new drugs never reach the market or are withdrawn post-marketing. Unfortunately, it remains impossible to predict accurately which new drugs will cause DILD and who will be at risk of developing this disease. This is due in large part to the idiosyncratic nature of most cases of DILD and the lack of animal models, which are vital for uncovering fundamental mechanisms of toxicity. Nevertheless, earlier studies in mice indicate that reactive metabolites and protein adducts of drugs may be major initiators of both allergic and non-allergic DILD. More recently, we have found that the hepatotoxic potential of drugs can be amplified when deficiencies exist in one or more immune regulatory factors that protect liver including interleukins -4, -6, -10, and -13, and prostaglandins, which in many cases are produced by Kupffer cell in the liver. On the other hand, protoxicant factors such as macrophage migration inhibitory protein and osteopontin, which can activate the innate immune system, exacerbate DILD. As a result, the incidence and severity of DILD is likely determined in part by the balance between these opposing classes of regulatory factors. Global genomic and proteomic methods have been used by us in other studies in mice to discover additional potential risk factors that may help explain susceptibility differences of both mouse strains and humans to DILD.

In addition, we have found that when the liver is injured by drugs the hypothalamic-pituitary-adrenal axis is activated to produce widespread transient lymphocytolysis and immunological tolerance. This response to liver injury might help explain why drug-induced allergic hepatitis, which appears to be driven by an immune response against drug-protein adducts, is a rare disease. Similarly, we have reported that Kupffer cells may also have a role in inducing tolerance against drug-protein adducts released from damaged hepatocytes.

Our findings suggest that variant genes of one or more protective and/or protoxicant factors or possibly their receptors as well as environmental factors affecting the levels and activities of these modulatory molecules may be risk factors that contribute to the incidence of DILD in patients.

Each problem studied in the laboratory is approached utilizing modern techniques of toxicology, biochemistry, immunology, cellular biology, molecular biology, genomics, proteomics, bioinformatics, and systems biology. Our long term goals are to translate our findings into new approaches for identifying patients who are susceptible to DILD and for designing safer drugs and treatments for DILD.

Postdoctoral Position at the NIH, Drug-Induced Liver Disease (Summer 2008)

Section Members:

Selected Publications:

1. Yee, S.B., Bourdi, M., Masson, M.J., and Pohl, L.R.: Hepatoprotective role of endogenous interleukin-13 in a murine model of acetaminophen-induced liver disease. Chem. Res. Toxicol. 20, 734-744 (2007).
2. Bourdi, M., Eiras, D.P., Holt, M.P., Webster, M.R., Reilly, T.P., Welch, K.D., and Pohl, L.R.: Role of IL-6 in an IL-10 and IL-4 double knockout mouse model uniquely susceptible to acetaminophen-induced liver injury. Chem. Res. Toxicol. 20, 208-216 (2007).
3. Masson, M.J., Peterson R.A., Chung, C.J., Graf, M.L., Carpenter, L.D., Ambroso, J.L., Krul, D. L., Sciarrotta, J., and Pohl, L.R.: Lymphocyte loss and immunosuppression following acetaminophen-induced hepatotoxicity in mice as a potential mechanism of tolerance. Chem. Res. Toxicol., 20, 20-27 (2007).
4. Welch, K.D., Reilly, T.P., Bourdi, M., Hays, T., Pise-Masison, C.A., Radonovich, M.F., Brady, J.N., Dix, D.J., and Pohl, L.R.: Chem. Res. Toxicol. Genomic identification of potential risk factors during acetaminophen-induced liver disease in susceptible and resistant strains of mice. Chem. Res. Toxicol., 19, 223-233 (2006).
5. Welch, K.D, Wen, B., Goodlett, D.R., Yi, E.C., Lee, H., Reilly, T.P., Nelson, S.D., and Pohl, L.R.: Proteomic identification of potential susceptibility factors in drug-induced liver disease. Chem. Res. Toxicol., 18, 924-933 (2005).
6. Lee, H., Yi, E.C., Wen, B. Reilly, T.P., Pohl, L, Nelson, S., Aebersold, R., and Goodlett, D.R.: Optimization of reversed-phase microcapillary liquid chromatography for quantitative proteomics. J. Chromatogr. B. Biomed. Sci. Appl., 803, 101-110 (2004).
7. Ju, C., McCoy, J.P., Chung, C.J., Graf, M.L.M., and Pohl, L.R.: Tolerogenic role of Kupffer cells in allergic reactions. Chem. Res. Toxicol., 16, 1514-1519 (2003).
8. Masubuchi, Y., Bourdi, M., Reilly, T.P., Graf, M.L.M., George, J.W. and Pohl, L.R.: Role of interleukin-6 in hepatic heat shock protein expression and protection against acetaminophen-induced liver disease. Biochem. Biophys. Res. Comm. 304, 207-212 (2003).
9. Ju, C., Reilly, T.P., Bourdi, M., Radonovich, M.F., Brady, J.N., George, J.W., and Pohl, L.R.: Protective role of Kupffer cells in acetaminophen-induced hepatic injury in mice. Chem. Res. Toxicol. 15, 1504-1513 (2002).
10. Bourdi, M., Reilly, T.P., Elkahloun, A.G., George, J.W., and Pohl, L.R.: Macrophage migration inhibitory factor in drug-induced liver injury: A role in susceptibility and stress responsiveness. Biochem. Biophys. Res. Comm. 294: 225-230 (2002).
11. Bourdi, M., Masubuchi, Y., Reilly, T.P., Amouzadeh, H.R., Martin, J.L., George, J.W., Shah, A.G., and Pohl, L.R: Protection against Acetaminophen-Induced Liver Injury and Lethality by Interleukin-10. Role Of Inducible Nitric Oxide Synthase. Hepatology 35: 289-298 (2002).
12. Njoku, D.B., Greenberg, R.S., Bourdi, M., Borkowf, C. B., Dake, E.M., Martin, J.L., and Pohl, L.R.: Autoantibodies associated with volatile anesthetic hepatitis found in the sera of a large cohort of pediatric anesthesiologists. Anesth. Analg. 94: 243-249 (2002).
13. Njoku, D.B., Shrestha, S., Soloway, R., Duray, P.R., Tsokos, M., Abu-Asab, M.S., Pohl, L.R., and West, A.B.: Subcellular localization of trifluoroacetylated liver proteins in association with hepatitis following isoflurane. Anesthesiology 96: 757-761 (2002).
14. Reilly, T.P., Brady, J.N., Marchick, M., Bourdi, M., George, J.W., Rodonovich, M.F., Pise-Masison, C.A., and Pohl, L.R.: A protective role for cyclooxygenases in drug-induced liver injury in mice. Chem. Res. Toxicol. 14: 1620-1628 (2001).
15. Ju, C. and Pohl, L.R.: Immunohistochemical Detection of Protein Adducts of 2, 4-Dinitrochlorobenzene in Antigen Presenting Cells and Lymphocytes of Mice: Lack of Role of Kupffer Cells in Oral Tolerance. Chem. Res. in Toxicol. 14: 1209-1217 (2001).
16. Keegan, M.T., Martin, J.L., Vasdev, G.M.S., Bourdi, M., Pohl, L.R., and Plevak, D.J.: Fatal hepatitis associated with isoflurane exposure and CYP2A6 autoantibodies. Anesthesiology 95: 551-553 (2001).
17. Bourdi, M., Amouzadeh, H.R., Rushmore, T.H., Martin, J.L., and Pohl, L.R.: Halothane-Induced Liver Injury in Outbred Guinea Pigs: Role of Trifluoroacetylated Protein Adducts in Animal Susceptibility. Chem. Res. Toxicol. 14: 362-370 (2001).
18. Reilly, T.P., Bourdi, M., Brady, J.N., Pise-Masison, C.A., Radonovich, M.F., George, J.W., and Pohl, L.R.: Expression profiling of acetaminophen liver toxicity in mice using microarray technology. Biochem. Biophys. Res. Comm. 282: 321-328 (2001).