Update on Advances in Research on Idiosyncratic Drug-Induced Liver Injury

Abstract

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Drug-induced liver injury (DILI) is a major concern for public health, as well as for drug development in the pharmaceutical industry, since it can cause liver failure and lead to drug withdrawal from the market and black box warnings. Thus, it is important to identify biomarkers for early prediction to increase our understanding of mechanisms underlying DILI that will ultimately aid in the exploration of novel therapeutic strategies to prevent or manage DILI. DILI can be subdivided into 'intrinsic' and 'idiosyncratic' categories, although the validity of this classification remains controversial. Idiosyncratic DILI occurs in a minority of susceptible individuals with a prolonged latency, while intrinsic DILI results from drug-induced direct hepatotoxicity over the course of a few days. The rare occurrence of idiosyncratic DILI requires multicenter collaborative investigations and phenotype standardization. Recent progress in research on idiosyncratic DILI is based on key developments in 3 areas: (1) newly developed highthroughput genotyping across the whole genome allowing for the identification of genetic susceptibility markers, (2) new mechanistic concepts on the pathogenesis of DILI revealing a key role of drug-responsive T lymphocytes in the immunological response, and (3) broad multidisciplinary approaches using different platform "-omics" technologies that have identified novel biomarkers for the prediction of DILI. An association of a specific human leukocyte antigen (HLA) allele with DILI has been reported for several drugs. HLA-restricted T-cell immune responses have also been investigated using lymphocytes and T-cell clones isolated from patients. A microRNA, miR-122, has been discovered as a promising biomarker for the early prediction of DILI. In this review, we summarize recent advances in research on idiosyncratic DILI with an understanding of the key role of adaptive immune systems.

Do In Vitro Assays Predict Drug Candidate Idiosyncratic Drug-Induced Liver Injury Risk?

“…Perhaps the most compelling evidence that RMs may play an important mechanistic role has been provided by the demonstration of drug-related adaptive immune responses in patients with iDILI caused by numerous drugs, but not in drug-treated patients who do not exhibit iDILI. The immune responses include serum autoantibodies to P450s that metabolize the drugs and to other liver proteins, antibodies to drug adductmodified liver proteins, and drug-specific T-cell responses (Kim and Naisbitt, 2016).…”

Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back–Looking Forward to Next-Generation Innovation

“…GWASs for idiosyncratic DIH remain challenging because it is a rare condition, and there are phenotypic variations and ethnic diversity (Kim and Naisbitt, 2016). The sample size limitation is magnified when performing GWASs for idiosyncratic DIH because it requires sufficiently large study subjects to reach a genome-wide significance level.…”

“…The sample size limitation is magnified when performing GWASs for idiosyncratic DIH because it requires sufficiently large study subjects to reach a genome-wide significance level. To overcome this limitation, multicenter research networks have been established, namely DILIN-Drug-Induced Liver Injury Network in United States; DILIGEN-a study on the genetics of drug-related liver disease in United Kingdom; EUDRAGENE-in Europe; DILI registry-in Spain; and others (Kim and Naisbitt, 2016). By establishing collaboration and combining cohorts from multiple sites, large-scale GWASs can have higher power to detect and validate the risk variants for DIH.…”

Serum miR‐122 and miR‐192 as biomarkers of intrinsic and idiosyncratic acute hepatotoxicity: A quantitative real‐time polymerase chain reaction study in adult albino rats

“…There are two main forms of toxic liver injury (TLI); first, a dose‐dependent intrinsic TLI as occur with acetaminophen (APAP); a widely used analgesic which produces acute TLI in overdose. Second, a dose‐independent idiosyncratic TLI which is unpredictable and can occur at therapeutic doses as in diclofenac (DCLF), a nonsteroidal anti‐inflammatory drug …”