Zidovudine (AZT) and hepatic lipid accumulation: implication of inflammation, oxidative and endoplasmic reticulum stress mediators
Open accessAbstract
The clinical effectiveness of Zidovudine (AZT) is constrained due to its side-effects including hepatic steatosis and toxicity. However, the mechanism(s) of hepatic lipid accumulation in AZT-treated individuals is unknown. We hypothesized that AZT-mediated oxidative and endoplasmic reticulum (ER) stress may play a role in the AZT-induced hepatic lipid accumulation. AZT treatment of C57BL/6J female mice (400 mg/day/kg body weight, i.p.) for 10 consecutive days significantly increased hepatic triglyceride levels and inflammation. Markers of oxidative stress such as protein oxidation, nitration, glycation and lipid peroxidation were significantly higher in the AZT-treated mice compared to vehicle controls. Further, the levels of ER stress marker proteins like GRP78, p-PERK, and p-eIF2α were significantly elevated in AZT-treated mice. The level of nuclear SREBP-1c, a transcription factor involved in fat synthesis, was increased while significantly decreased protein levels of phospho-acetyl-CoA carboxylase, phospho-AMP kinase and PPARα as well as inactivation of 3-keto-acyl-CoA thiolase in the mitochondrial fatty acid β-oxidation pathway were observed in AZT-exposed mice compared to those in control animals. Collectively, these data suggest that elevated oxidative and ER stress plays a key role, at least partially, in lipid accumulation, inflammation and hepatotoxicity in AZT-treated mice.
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Acute or sub-chronic exposure to various hepatotoxic compounds, including APAP, tamoxifen, AZT and antidepressants, can cause mitochondrial dysfunction, contributing to liver injury with or without fat accumulation.
“In addition, acute or sub-chronic exposure to various hepatotoxic compounds, including clinically-used drugs, such as acetaminophen (APAP) [18], [19], [20], a major ingredient of Tylenol®, an anti-breast cancer agent tamoxifen [21], an anti-retroviral drug zidovudine (AZT) [22] and antidepressants [23], can cause mitochondrial dysfunction, contributing to”
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References 60 · Cited by 35
- Authors
- Banerjee, A., Abdelmegeed, M. A., Jang, S., & Song, B.-J.
- Affiliations
- National Institute on Alcohol Abuse and Alcoholism (US)
- Corresponding author
- Song, Byoung-Joon
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-10-11
- Volume
- 8
- Issue
- 10
- Pages
- e76850
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3795627
- OpenAlex
- W2054473208
- Cited by
- 35
- References
- 60
- Citations by year
- 2025: 2 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 2 · 2018: 2 · 2017: 4 · 2016: 4 · 2015: 6 · 2014: 4
- FWCI
- 5.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Keywords
- zidovudine, hepatic steatosis, hepatic lipid accumulation, oxidative stress, endoplasmic reticulum stress, hepatotoxicity, liver inflammation, SREBP-1c, fatty acid beta-oxidation, PPARα, AMPK, acetyl-CoA carboxylase, GRP78, PERK, eIF2α, triglycerides, antiretroviral therapy adverse effects
- MeSH terms
- Endoplasmic Reticulum Chaperone BiP, Animals, Female, Inflammation, Liver, Mice, Inbred C57BL, Models, Biological, Oxidation-Reduction, Protein Processing, Post-Translational, Zidovudine, Biomarkers, Cytochrome P-450 CYP2E1, Cytochrome P-450 CYP4A, Lipid Metabolism, Mice, Cytochrome P-450 CYP3A, Endoplasmic Reticulum Stress
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