PMID- 33799477
OWN - NLM
STAT- MEDLINE
DCOM- 20210430
LR  - 20210430
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 6
DP  - 2021 Mar 14
TI  - Idiosyncratic Drug-Induced Liver Injury: Mechanistic and Clinical Challenges.
LID - 10.3390/ijms22062954 [doi]
LID - 2954
AB  - Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for 
      patients and drug development. The idiosyncratic nature of IDILI makes 
      mechanistic studies difficult, and little is known of its pathogenesis for 
      certain. Circumstantial evidence suggests that most, but not all, IDILI is caused 
      by reactive metabolites of drugs that are bioactivated by cytochromes P450 and 
      other enzymes in the liver. Additionally, there is overwhelming evidence that 
      most IDILI is mediated by the adaptive immune system; one example being the 
      association of IDILI caused by specific drugs with specific human leukocyte 
      antigen (HLA) haplotypes, and this may in part explain the idiosyncratic nature 
      of these reactions. The T cell receptor repertoire likely also contributes to the 
      idiosyncratic nature. Although most of the liver injury is likely mediated by the 
      adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune 
      activation first requires an innate immune response to activate antigen 
      presenting cells and produce cytokines required for T cell proliferation. This 
      innate response is likely caused by either a reactive metabolite or some form of 
      cell stress that is clinically silent but not idiosyncratic. If this is true it 
      would make it possible to study the early steps in the immune response that in 
      some patients can lead to IDILI. Other hypotheses have been proposed, such as 
      mitochondrial injury, inhibition of the bile salt export pump, unfolded protein 
      response, and oxidative stress although, in most cases, it is likely that they 
      are also involved in the initiation of an immune response rather than 
      representing a completely separate mechanism. Using the clinical manifestations 
      of liver injury from a number of examples of IDILI-associated drugs, this review 
      aims to summarize and illustrate these mechanistic hypotheses.
FAU - Jee, Alison
AU  - Jee A
AUID- ORCID: 0000-0002-8136-0002
AD  - Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 
      1A8, Canada.
FAU - Sernoskie, Samantha Christine
AU  - Sernoskie SC
AUID- ORCID: 0000-0002-0904-8516
AD  - Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON M5S 
      3M2, Canada.
FAU - Uetrecht, Jack
AU  - Uetrecht J
AD  - Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 
      1A8, Canada.
AD  - Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON M5S 
      3M2, Canada.
LA  - eng
GR  - 142329/CAPMC/CIHR/Canada
PT  - Journal Article
PT  - Review
DEP - 20210314
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Cytokines)
RN  - 0 (Receptors, Antigen, T-Cell)
SB  - IM
MH  - CD8-Positive T-Lymphocytes/drug effects/immunology
MH  - Chemical and Drug Induced Liver Injury/*immunology/pathology
MH  - Cytokines/genetics
MH  - Humans
MH  - Immunity, Innate/genetics/*immunology
MH  - Liver/drug effects/*immunology
MH  - Lymphocyte Activation/immunology
MH  - Receptors, Antigen, T-Cell/*genetics/immunology
PMC - PMC7998339
OTO - NOTNLM
OT  - adverse drug reactions
OT  - cytochromes P450
OT  - damage-associated molecular pattern molecules
OT  - immunotoxicity
OT  - innate immune response
OT  - liver injury
OT  - reactive metabolites
COIS- The authors have no conflict of interest to declare.
EDAT- 2021/04/04 06:00
MHDA- 2021/05/01 06:00
PMCR- 2021/03/14
CRDT- 2021/04/03 01:02
PHST- 2021/02/16 00:00 [received]
PHST- 2021/03/08 00:00 [revised]
PHST- 2021/03/11 00:00 [accepted]
PHST- 2021/04/03 01:02 [entrez]
PHST- 2021/04/04 06:00 [pubmed]
PHST- 2021/05/01 06:00 [medline]
PHST- 2021/03/14 00:00 [pmc-release]
AID - ijms22062954 [pii]
AID - ijms-22-02954 [pii]
AID - 10.3390/ijms22062954 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Mar 14;22(6):2954. doi: 10.3390/ijms22062954.