FXR: Big fish or small fry for drug-induced liver injury?

By integrating network analysis and molecular modeling, a "system pharmacology" approach identified FXR as a potential off-target protein mediating non-steroidal anti-inflammatory drugs (NSAID)-induced liver injury. In vitro assays showed that NSAID are potent FXR antagonists that inhibit FXR transcriptional activity. Given the role of FXR in bile acid homeostasis, liver inflammation and cell proliferation, the data suggest that FXR antagonism could mediate, at least in part, NSAID-induced liver injury.

Preventing Drug-Induced Liver Injury: How Useful Are Animal Models?

Drug-induced liver injury (DILI) is the most common organ toxicity encountered in regulatory animal toxicology studies required prior to the clinical development of new drug candidates. Very few reports have evaluated the value of these studies for predicting DILI in humans. Indeed, compounds inducing liver toxicity in regulatory toxicology studies are not always correlated with a risk of DILI in humans.

Back to basics for idiosyncratic drug-induced liver injury: dose and metabolism make the poison.

Two studies show that the risk of drug-induced liver injury (DILI) is increased when the daily dose of a drug given by oral route is higher than 10mg per day and/or when the drug undergoes a significant hepatic metabolism. If confirmed, these data suggest that developing drugs with high potency and low hepatic metabolism will reduce the risk of idiosyncratic DILI in man.

Vesicular transport of newly synthesized cytochromes P4501A to the outside of rat hepatocyte plasma membranes.

Anti-cytochrome P450 (CYP)1A2 autoantibodies are found in dihydralazine-induced hepatitis, and CYPs2B and 2C have been shown to follow vesicular flow to the plasma membrane (PM). However, it is unknown whether other CYPs follow this route, whether NADPH-CYP reductase is present on the hepatocyte surface, and whether autoimmune hepatitis-inducing drugs increase PM CYPs. In this study, we determined the transmembrane topology and transport of CYPs1A in rat hepatocytes.

Phase I and phase II drug-metabolizing enzymes are expressed and heterogeneously distributed in the biliary epithelium.

Tissue expression of drug-metabolizing enzymes influences susceptibility to drugs and carcinogens. Because the biliary epithelium, exposed to bile-borne chemicals, may give rise to drug-induced cholangiopathies and to cholangiocarcinomas, we determined the pattern of expression of drug-metabolizing enzymes in this epithelium. We first demonstrated by blot analyses that biliary epithelial cells (BEC) isolated from human gallbladders display cytochrome P450 (CYP) 1A, 2E1, and 3A, microsomal epoxide hydrolase (mEH), alpha, mu, and pi glutathione S-transferase (GST), transcripts and proteins.