Idiosyncratic Drug-Induced Liver Injury (IDILI): Potential Mechanisms and Predictive Assays

Abstract

Idiosyncratic drug-induced liver injury (IDILI) is a significant source of drug recall and acute liver failure (ALF) in the United States. While current drug development processes emphasize general toxicity and drug metabolizing enzyme- (DME-) mediated toxicity, it has been challenging to develop comprehensive models for assessing complete idiosyncratic potential. In this review, we describe the enzymes and proteins that contain polymorphisms believed to contribute to IDILI, including ones that affect phase I and phase II metabolism, antioxidant enzymes, drug transporters, inflammation, and human leukocyte antigen (HLA). We then describe the various assays that have been developed to detect individual reactions focusing on each of the mechanisms described in the background. Finally, we examine current trends in developing comprehensive models for examining these mechanisms. There is an urgent need to develop a panel of multiparametric assays for diagnosing individual toxicity potential.

Figure 1

Simplified mechanisms of drug metabolism in liver cells with potential pathways towards toxicity. Abbreviations are used as follows: Na⁺-taurocholate cotransporting polypeptide (NTCP), organic cation transporter (OCT), organic anion transporting polypeptide (OATP), bile salt export pump (BSEP), breast cancer resistance protein (BCRP), multidrug resistance protein (MDR), multidrug resistance-associated protein (MRP), cytochrome P450 (CYP), flavin-containing monooxygenase (FMO), monoamine oxidase (MAO), UDP-glucuronosyltransferases (UGT), sulfotransferase (SULT), glutathione S-transferase (GST), N-acetyl transferase (NAT), reactive oxygen species (ROS), reactive nitrogen species (RNS), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), mitochondrial pore transition (MPT), mitochondrial DNA (mtDNA), receptor-interacting serine/threonine protein kinase (RIPK), phosphoglycerate mutase (PGAM), c-Jun N-terminal kinase (JNK), B-cell lymphoma 2 (Bcl2), antigen-presenting cell (APC), and Kupffer cell (KC) [12].

Figure 2

Mechanisms of mediating ROS within the liver. Abbreviations are used as follows: superoxide dismutase (SOD), catalase (CAT), peroxiredoxin (Prx), thioredoxin (Trx), thioredoxin reductase (TrxR), glutathione peroxidase (GPx), glutathione (GSH), and glutathione disulfide (GSSG).

Figure 3

Transporter mechanisms on the cell membranes of hepatocytes. Proteins that are labeled yellow have known clinically relevant polymorphisms, while green labeled proteins do not have known clinically relevant polymorphisms. Abbreviations are used as follows: organic cation transporter (OCT), organic anion transporter (OAT), organic anion transporting polypeptide (OATP), Na⁺-taurocholate cotransporting polypeptide (NTCP), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance protein (MDR), multidrug resistance-associated protein (MRP), organic solute transporter (OST), and multidrug and toxin extrusion protein (MATE) [13].

Figure 4

Simplified mechanisms of inflammation signaling caused by adverse drug reactions (ADRs) in the liver. Abbreviations are used as follows: toll-like receptor (TLR), major histocompatibility complex (MHC), T cell receptor (TCR), drug metabolizing enzymes (DMEs), antigen-presenting cell (APC), cytotoxic T lymphocyte (T_C cell), and helper T lymphocyte (T_H cell).

Figure 5

Metabolism of coumarin by CYP450 isoforms. Abbreviations are used as follows: 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin (AMMC), and 3-[2-(N,N-diethylamino)ethyl]-7-hydroxy-4-methylcoumarin (AHMC).

Figure 6

Hepatic cell coculture systems with applications in hepatotoxicity: (a) porous nylon membrane scaffold system [192], (b) the microfluidic system [193, 194], and (c) micropatterned hepatic cocultures [195].