Drug-induced hepatic steatosis in absence of severe mitochondrial dysfunction in HepaRG cells: proof of multiple mechanism-based toxicity

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease in developed countries. Its frequency is increasing in the general population mostly due to the widespread occurrence of obesity and the metabolic syndrome. Although drugs and dietary supplements are viewed as a major cause of acute liver injury, drug induced steatosis and steatohepatitis are considered a rare form of drug induced liver injury (DILI). The complex mechanism leading to hepatic steatosis caused by commonly used drugs such as amiodarone, methotrexate, tamoxifen, valproic acid, glucocorticoids, and others is not fully understood. It relates not only to induction of the metabolic syndrome by some drugs but also to their impact on important molecular pathways including increased hepatocytes lipogenesis, decreased secretion of fatty acids, and interruption of mitochondrialβ-oxidation as well as altered expression of genes responsible for drug metabolism. Better familiarity with this type of liver injury is important for early recognition of drug hepatotoxicity and crucial for preventing severe forms of liver injury and cirrhosis. Moreover, understanding the mechanisms leading to drug induced hepatic steatosis may provide much needed clues to the mechanism and potential prevention of the more common form of metabolic steatohepatitis.

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Drug-induced effects on mtDNA homeostasis in HepaRG cells and modulation by steatosis

Journal of Hepatology ◽

10.1016/s0168-8278(17)31149-2 ◽

2017 ◽

Vol 66 (1) ◽

pp. S397

Author(s):

D. Le Guillou ◽

S. Bucher ◽

D. Hoët ◽

G. Labbe ◽

B. Fromenty

Keyword(s):

Drug Induced ◽

Heparg Cells

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Mitochondrial Dysfunction in Drug-Induced Liver Injury

Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants ◽

10.1002/9781119329725.ch5 ◽

2018 ◽

pp. 47-72

Author(s):

Annie Borgne-Sanchez ◽

Bernard Fromenty

Keyword(s):

Liver Injury ◽

Mitochondrial Dysfunction ◽

Drug Induced ◽

Drug Induced Liver Injury

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Medication Bezoar with Extended-Release Nifedipine/Biliary Cirrhosis Caused by Erythromycin/Four Cases of Lactic Acidosis and Hepatic Steatosis Associated with Stavudine Therapy/Acute Myelopathy following Heroin Insufflation/Increased Lithium Concentrations with a “Safe” NSAID/Drug-Induced Stroke and Complications of Intravesical Bacillus Calmette-Guerin

Hospital Pharmacy ◽

10.1177/001857870003501012 ◽

2000 ◽

Vol 35 (10) ◽

pp. 1046-1050

Author(s):

Joel Shuster

Keyword(s):

Lactic Acidosis ◽

Hepatic Steatosis ◽

Extended Release ◽

Biliary Cirrhosis ◽

Bacillus Calmette Guerin ◽

Drug Induced ◽

Acute Myelopathy

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Zucker Lean Rats With Hepatic Steatosis Recapitulate Asymptomatic Metabolic Syndrome and Exhibit Greater Sensitivity to Drug-Induced Liver Injury Compared With Standard Nonclinical Sprague-Dawley Rat Model

Toxicologic Pathology ◽

10.1177/0192623320968716 ◽

2020 ◽

Vol 48 (8) ◽

pp. 994-1007

Author(s):

Timothy P. LaBranche ◽

Anna K. Kopec ◽

Srinivasa R. Mantena ◽

Brett D. Hollingshead ◽

Andrew W. Harrington ◽

...

Keyword(s):

Metabolic Syndrome ◽

Pharmaceutical Industry ◽

Liver Injury ◽

Hepatic Steatosis ◽

Sprague Dawley ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Sd Rats ◽

Normal Chow

Fatty liver disease is a potential risk factor for drug-induced liver injury (DILI). Despite advances in nonclinical in vitro and in vivo models to assess liver injury during drug development, the pharmaceutical industry is still plagued by idiosyncratic DILI. Here, we tested the hypothesis that certain features of asymptomatic metabolic syndrome (namely hepatic steatosis) increase the risk for DILI in certain phenotypes of the human population. Comparison of the Zucker Lean (ZL) and Zucker Fatty rats fed a high fat diet (HFD) revealed that HFD-fed ZL rats developed mild hepatic steatosis with compensatory hyperinsulinemia without increases in liver enzymes. We then challenged steatotic HFD-fed ZL rats and Sprague-Dawley (SD) rats fed normal chow, a nonclinical model widely used in the pharmaceutical industry, with acetaminophen overdose to induce liver injury. Observations in HFD-fed ZL rats included increased liver injury enzymes and greater incidence and severity of hepatic necrosis compared with similarly treated SD rats. The HFD-fed ZL rats also had disproportionately higher hepatic drug accumulation, which was linked with abnormal hepatocellular efflux transporter distribution. Here, we identify ZL rats with HFD-induced hepatic steatosis as a more sensitive nonclinical in vivo test system for modeling DILI compared with SD rats fed normal chow.

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Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: A Systematic Review

Antioxidants ◽

10.3390/antiox8040109 ◽

2019 ◽

Vol 8 (4) ◽

pp. 109 ◽

Cited By ~ 14

Author(s):

Chisato Fujimoto ◽

Tatsuya Yamasoba

Keyword(s):

Oxidative Stress ◽

Hearing Loss ◽

Mitochondrial Dysfunction ◽

Cell Lines ◽

Mitochondrial Gene ◽

Protective Effects ◽

Drug Induced ◽

Age Related ◽

Cochlear Damage ◽

Age Related Hearing Loss

Mitochondrial dysfunction is associated with the etiologies of sensorineural hearing loss, such as age-related hearing loss, noise- and ototoxic drug-induced hearing loss, as well as hearing loss due to mitochondrial gene mutation. Mitochondria are the main sources of reactive oxygen species (ROS) and ROS-induced oxidative stress is involved in cochlear damage. Moreover, the release of ROS causes further damage to mitochondrial components. Antioxidants are thought to counteract the deleterious effects of ROS and thus, may be effective for the treatment of oxidative stress-related diseases. The administration of mitochondria-targeted antioxidants is one of the drug delivery systems targeted to mitochondria. Mitochondria-targeted antioxidants are expected to help in the prevention and/or treatment of diseases associated with mitochondrial dysfunction. Of the various mitochondria-targeted antioxidants, the protective effects of MitoQ and SkQR1 against ototoxicity have been previously evaluated in animal models and/or mouse auditory cell lines. MitoQ protects against both gentamicin- and cisplatin-induced ototoxicity. SkQR1 also provides auditory protective effects against gentamicin-induced ototoxicity. On the other hand, decreasing effect of MitoQ on gentamicin-induced cell apoptosis in auditory cell lines has been controversial. No clinical studies have been reported for otoprotection using mitochondrial-targeted antioxidants. High-quality clinical trials are required to reveal the therapeutic effect of mitochondria-targeted antioxidants in terms of otoprotection in patients.

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Assessment of the impact of mitochondrial genotype upon drug-induced mitochondrial dysfunction in platelets derived from healthy volunteers

Archives of Toxicology ◽

10.1007/s00204-021-02988-3 ◽

2021 ◽

Author(s):

Amy L. Ball ◽

Katarzyna M. Bloch ◽

Lucille Rainbow ◽

Xuan Liu ◽

John Kenny ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Healthy Volunteers ◽

Adverse Drug Reactions ◽

Mitochondrial Function ◽

Flux Analysis ◽

Drug Reactions ◽

Drug Induced ◽

Mtdna Variation ◽

Mitochondrial Genotype ◽

The Impact

AbstractMitochondrial DNA (mtDNA) is highly polymorphic and encodes 13 proteins which are critical to the production of ATP via oxidative phosphorylation. As mtDNA is maternally inherited and undergoes negligible recombination, acquired mutations have subdivided the human population into several discrete haplogroups. Mitochondrial haplogroup has been found to significantly alter mitochondrial function and impact susceptibility to adverse drug reactions. Despite these findings, there are currently limited models to assess the effect of mtDNA variation upon susceptibility to adverse drug reactions. Platelets offer a potential personalised model of this variation, as their anucleate nature offers a source of mtDNA without interference from the nuclear genome. This study, therefore, aimed to determine the effect of mtDNA variation upon mitochondrial function and drug-induced mitochondrial dysfunction in a platelet model. The mtDNA haplogroup of 383 healthy volunteers was determined using next-generation mtDNA sequencing (Illumina MiSeq). Subsequently, 30 of these volunteers from mitochondrial haplogroups H, J, T and U were recalled to donate fresh, whole blood from which platelets were isolated. Platelet mitochondrial function was tested at basal state and upon treatment with compounds associated with both mitochondrial dysfunction and adverse drug reactions, flutamide, 2-hydroxyflutamide and tolcapone (10–250 μM) using extracellular flux analysis. This study has demonstrated that freshly-isolated platelets are a practical, primary cell model, which is amenable to the study of drug-induced mitochondrial dysfunction. Specifically, platelets from donors of haplogroup J have been found to have increased susceptibility to the inhibition of complex I-driven respiration by 2-hydroxyflutamide. At a time when individual susceptibility to adverse drug reactions is not fully understood, this study provides evidence that inter-individual variation in mitochondrial genotype could be a factor in determining sensitivity to mitochondrial toxicants associated with costly adverse drug reactions.

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