Role of Inflammation in Metabolism and Hepatotoxicity of Prototypical Drugs



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Inflammation leads to altered drug metabolism and augments drug-induced hepatotoxicity. However, the mechanisms are not fully understood. Inflammation is known to alter the gene expression and activity of several key drug metabolizing enzymes (DMEs) further compromising the safety and efficacy of drugs. Inflammatory responses in the liver are primarily mediated by the Toll-like receptors (TLRs), found on the cell surface of hepatocytes and immune cells, such as Kupffer cells. TLR2 and TLR4, upon activation recruit the first adaptor molecule, the Toll-interleukin 1 receptor adaptor protein (TIRAP). TIRAP was shown to play a differential role in regulating gene expression of Cyp3a11 in lipopolysaccharide- (LPS, TLR4 agonist) or lipoteichoic acid- (LTA, TLR2 agonist) induced inflammation in mice. In this project, we studied the role of the TLR signaling pathway in regulating inflammation-mediated altered drug metabolism and hepatotoxicity of prototypical drugs in mice. Aim 1: We observed significant down-regulation of Cyp3a11 protein expression and activity (measured by midazolam (MDZ) metabolism) in LPS- or LTA-induced inflammation. This further correlated with reduced clearance and increased pharmacological action of MDZ in both, LPS- or LTA-treated mice. In contrast to LPS, TIRAP was involved only in LTA-mediated down regulation of Cyp3a11 and metabolism of MDZ. Aim 2: We studied the effects of inflammation and the TLR signaling pathway in regulating hepatotoxicity of chlorpromazine (CPZ). We selected CPZ due to its idiosyncratic hepatotoxicity reported in humans and animals. Sustained activation of the kinase, c-Jun-N-terminal kinase (JNK) is associated with cell death. However, the roles of JNK and TIRAP in regulating CPZ-induced hepatotoxicity in presence of inflammation are unknown. In our in vivo study, LPS or LTA treatment led to significant induction of CPZ hepatotoxicity with increase in serum tumor necrosis factor (TNF)-α and sustained activation of JNK upto 4 h. Histopathological analysis revealed marked depletion of hepatic glycogen in LPS/CPZ or LTA/CPZ groups. Also, CPZ-induced hepatotoxicity, increase in serum TNF-α and activation of JNK in presence of LPS or LTA were dependent on TIRAP. In our in vitro study, we observed significant induction of alanine aminotransferase (ALT) in CPZ-treated primary mouse hepatocytes in presence of LPS or LTA. We observed prolonged activation of JNK in presence TNF-α and TNF-α-mediated increase in ALT in presence of CPZ was attenuated by the JNK inhibitor. Overall, by focusing on the TLR signaling pathway, this dissertation provides novel insights in the underlying mechanisms involved in regulating drug metabolism and hepatotoxicity of prototypical drugs in inflammation.



Inflammation, Toll-like receptors, C-Jun-N-terminal kinase, Chlorpromazine, Acetaminophen, Midazolam, Cytochrome P4503A, Tumor necrosis factor-alpha, Lipopolysaccharide, Lipids, Lipoteichoic acid