Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis

Abstract

Idiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more than 50% of acute fulminant hepatic failure cases. In addition, approximately 30% of iDILI are cholestatic (drug-induced cholestasis (DIC)). The liver’s metabolism and clearance of lipophilic drugs depend on their emission into the bile. Therefore, many medications cause cholestasis through their interaction with hepatic transporters. The main canalicular efflux transport proteins include: 1. the bile salt export pump (BSEP) protein (ABCB11); 2. the multidrug resistance protein-2 (MRP2, ABCC2) regulating the bile salts’ independent flow by excretion of glutathione; 3. the multidrug resistance-1 protein (MDR1, ABCB1) that transports organic cations; 4. the multidrug resistance-3 protein (MDR3, ABCB4). Two of the most known proteins involved in bile acids’ (BAs) metabolism and transport are BSEP and MDR3. BSEP inhibition by drugs leads to reduced BAs’ secretion and their retention within hepatocytes, exiting in cholestasis, while mutations in the ABCB4 gene expose the biliary epithelium to the injurious detergent actions of BAs, thus increasing susceptibility to DIC. Herein, we review the leading molecular pathways behind the DIC, the links with the other clinical forms of familial intrahepatic cholestasis, and, finally, the main cholestasis-inducing drugs.

Liver Injury after Selective Androgen Receptor Modulator Intake: A Case Report and Review of the Literature

“…Furthermore, liver injury by SARM and AAS have very similar laboratory enzyme patterns with low transaminases, a predominant bilirubin elevation and a moderate elevation of alkaline phosphatase (AP), but normal gGT [30,31]. This reflects intrahepatic and canalicular trapping of bile salts, supposedly because of defective bile salt transport mechanisms [32]. Interestingly, in progressive familial intrahepatic cholestasis (PFIC), a similar histologi-cal and laboratory pattern is observed [32], pointing to similarities in disease pathomechanisms.…”

“…This reflects intrahepatic and canalicular trapping of bile salts, supposedly because of defective bile salt transport mechanisms [32]. Interestingly, in progressive familial intrahepatic cholestasis (PFIC), a similar histologi-cal and laboratory pattern is observed [32], pointing to similarities in disease pathomechanisms.…”

Qualitative and quantitative concentration-response modelling of gene co-expression networks to unlock hepatotoxic mechanisms for next generation chemical safety assessment

“…Interestingly, a decrease of the gene ABCB11 was seen at transcript level following CSA exposure at high concentrations above C max levels, which could potentially lead to lower BSEP levels and contribute to cholestasis. This is a counterintuitive response, as bile acids are known to induce ABCB11 expression (Vitale et al, 2023) although bile acids were not added to the medium and were not measured in the present study.…”

Systematic comparison of temporal transcriptional responses to hepatotoxicants in primary human hepatocytes and HepaRG cells using concentration-response modelling of gene co-expression networks

“…Interestingly, a decrease of the gene (ABCB11) was seen at transcript levels following CSA exposure at high concentrations above C max levels, which could potentially lead to lower BSEP levels and contribute to cholestasis. This is a counterintuitive response, as bile acids are known to induce ABCB11 expression (Vitale et al, 2023), although bile acids were not added to the medium and were not measured in the present study.…”