Abstract
The liver is the most important organ involved in the metabolism of virtually all drugs and xenobiotics introduced into the body. Drug-induced liver injury (DILI) is a major health problem. The hepatotoxicity associated with some drugs can be severe and life-threatening. DILI has been identified as the most frequent single incidence leading to the withdrawal or restricted use of marketed drugs or termination of clinical trials of investigational drugs during development. The pathogenesis of DILI is very complex. In addition to genetic and environmental factors, drug-induced hepatocyte injury plays a central role in the pathogenesis of DILI. During the last several decades, extensive research has been done to identify the molecular mechanisms underlying DILI. Emerging evidence indicates that endoplasmic reticulum (ER) stress is an important contributor to the pathogenesis of DILI by disrupting hepatic metabolism, inducing inflammation and cell apoptosis. In this chapter, we summarize the current understanding of ER stress in DILI with a focus on HIV protease inhibitor-induced hepatic injury.
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Abbreviations
- 3'UTR:
-
3′-untranslated region
- ABCB1:
-
ATP-binding cassette sub-family B member 1
- ABCC2:
-
ATP-binding cassette sub-family C member 2
- ALT:
-
Alanine aminotransferase
- AST:
-
Aspartate aminotransferase
- AP:
-
Alkaline phosphatase
- ATF:
-
Activating transcription factor
- AIDS:
-
Acquired human immunodeficiency syndrome
- BiP/GRP78:
-
Binding immunoglobulin protein/78 kDa glucose-regulated protein
- CHOP:
-
CCAAT enhancer-binding protein homologous protein
- CYP3A:
-
Cytochrome P450 3A4
- CYP7A1:
-
Cholesterol 7 alpha-hydroxylase
- DILI:
-
Drug-induced liver injury
- eIF2α:
-
Eukaryotic initiation factor 2 alpha
- ER:
-
Endoplasmic reticulum
- ERAD:
-
ER-associated degradation
- FDA:
-
The Food and Drug Administration
- HAART:
-
Highly active anti-retroviral therapy
- HIV-1:
-
Human immunodeficiency virus-1
- Insig:
-
The insulin-induced gene
- IRE1α:
-
Inositol requiring enzyme 1α
- LPS:
-
Lipopolysaccharide
- MRP2:
-
Multidrug resistance-associated protein 2
- PERK:
-
Protein kinase RNA–like endoplasmic reticulum kinase
- S1P:
-
Serine protease site-1 protease
- S2P:
-
Metalloprotease site-2 protease
- SCAP:
-
SREBP cleavage-activating protein
- SREBP:
-
Sterol regulatory element-binding proteins
- TLR4:
-
Toll-like receptor 4
- UPR:
-
Unfolded protein response
- XBP1:
-
X-box-binding protein 1
- XBP1s:
-
Spliced XBP1
- XBP1u:
-
Unspliced XBP1
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Acknowledgment
This study was supported by National Natural Science Foundation of China Grants (81070245 and 81270489 to HZ); National Institutes of Health Grants (R21AI068432; R01AT004148; 1R01DK104893; DK-057543), VA Merit Awards (I01BX001390); NIAAA 1F31AA024713; VCU Massey Cancer Pilot grant (A35362 to HZ). We would like to thank Elaine Studer Kennedy for English editing and proof-reading.
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Hinton, M., Li, Y., Kwong, E., Zhou, H. (2017). ER Stress in Drug-Induced Liver Injury. In: Ding, WX., Yin, XM. (eds) Cellular Injury in Liver Diseases. Cell Death in Biology and Diseases. Springer, Cham. https://doi.org/10.1007/978-3-319-53774-0_2
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