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Molecular and Cellulary Toxicology

Lance R Pohl, PharmD, PhD, Principal Investigator

Molecular and Cellulary Toxicology logoOur research focuses on the molecular and cellular basis of drug-induced liver disease (DILD), which is a major cause of life-threatening acute liver failure and is a key reason new drugs never reach the market or are withdrawn post-marketing.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, recent studies in mice indicate that DILD is a multistep process that can be initiated by reactive metabolites and protein-adducts of drugs and exacerbated by subsequent activation of the innate and adaptive immune systems. Our laboratory has been particularly interested in discovering regulatory pathways that counterbalance these hepatotoxic pathways. For example, we have found when drugs injure the liver there is a rapid upregulation and activation of numerous hepatoprotective factors including interleukins -4, -6, -10, and -13, prostaglandins and others factors that can either directly protect hepatocytes by activating cell defense signaling or indirectly protect hepatocytes by inhibiting the innate and adaptive immune systems. There is evidence for variant genes of one or more of these factors and their receptors being risk factors that determine susceptibility of patients to DILD.

Each problem in the laboratory is approached utilizing modern techniques of toxicology, biochemistry, immunology, cellular biology, molecular biology, genomics, epigenomics, 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 (Spring 2010)

Section Members:

Mohammed Bourdi, PhD
Staff Scientist
bourdim@nhlbi.nih.gov

Mala Chakraborty, PhD
Research Scientist
chakrabm@nhlbi.nih.gov

Pauline Ryan, PhD
Postdoctoral Fellow
Rynap3@nhlbi.nih.gov

Midhun Korrapati
Postdoctoral Fellow
korrapatim@nhlbi.nih.gov

John S. Davies, BS
Student Researcher
daviesjs@nhlbi.nih.gov

Nidhi Agrawal, BS
Student Researcher
Nidhi.agrawal@.nhlbi.nih.gov

Tami Graf, MS
Adjunct Investigator
graft@nhlbi.nih.gov

Mary Jane Masson, PhD
Adjunct Investigator
massonm@nhlbi.nih.gov

Steven B. Yee, PhD
Adjunct Investigator
yees@nhlbi.nih.gov

Selected Publications:

  1. Bourdi, M., Korrapati, M.C., Chakraborty, M., Yee, S.B., and Pohl, L.R.:  Protective Role of c-Jun N-Terminal Kinase 2 in Acetaminophen-Induced Liver Injury.  Biochem. Biophys. Res. Comm. 374, 6-10 (2008).
  2. Masson, M.J., Carpenter, L.D., Graf, M.L., and Pohl, L.R. : Pathogenic Role of NKT and NK Cells in Acetaminophen-Induced Liver Injury is Dependent on the Presence of DMSO.  Hepatology 48, 889-897 (2008).
  3. 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).
  4. 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).
  5. 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).
  6. 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).
  7. 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).
  8. 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).
  9. 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).
  10. 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).
  11. 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).
  12. 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).
  13. 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).
  14. 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).
  15. 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).
  16. 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).
  17. 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).
  18. 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).
  19. 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).
  20. 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).

 

 
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