Seminar given by Sungjoon Cho
Advisor: Dr. Hyun-Young Jeong
Biopharmaceutical Sciences, UIC
Abstract: Drug-induced liver injury (DILI) is the most common cause for liver failure and also the most common cause of failed drug approval. One of the major problems with DILI is the difficulty in identifying susceptible subjects and thus predicting DILI. Despite technical advances including genome-wide association study that allows us to identify genetic factors associated with higher risk for DILI, identification of an individual susceptible to severe DILI still remains difficult. This suggest that there are still unknown risk factors for DILI which constitutes a substantial gap in preventing DILI. The objective of this study is to determine the role of gut microbiota in modulating susceptibility to DILI using acetaminophen (APAP) as a model drug. APAP is a commonly used analgesic and a common cause of acute liver failure in the United States. Mechanisms of APAP-induced hepatotoxicity have been extensively studied, however, the unpredictability of severe liver injury after a given dose of APAP remains to be explained. To determine the role of gut microbiota in modulating APAP toxicity, we compared the susceptibility to APAP toxicity in C57BL/6 mice from two different vendors [Jackson (JAX) and Taconic (TAC)] which are known to have differential gut microbiota composition. TAC mice showed higher APAP toxicity compared to JAX mice which was abrogated upon cohousing, a process for assimilating gut microbiota composition. Additionally, Inoculation of cecum material from JAX or TAC mice to germ-free (GF) mice recapitulated the toxicity difference between JAX and TAC mice. These data suggest that differential gut microbiota modulates the susceptibility to APAP toxicity. To investigate which steps of APAP toxicity are altered by gut microbiota, a time-course experiment was performed in JAX and TAC mice. TAC mice showed faster and longer exposure to APAP-protein adduct in the liver which is consistent with higher APAP toxicity in TAC mice. TAC mice also showed higher CYP2E1 activity, a major enzyme responsible for bioactivation of APAP to a toxic metabolite. Taken together, our data indicate that differential gut microbiota modulates the susceptibility to APAP toxicity potentially by altering CYP2E1-mediated APAP bioactivation.
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Department of Biopharmaceutical Sciences