TAMH: A Useful In Vitro Model for Assessing Hepatotoxic Mechanisms

Davis, Madison J.; Stamper, Brendan D.

doi:10.1155/2016/4780872

Cited by 15 publications

(12 citation statements)

References 75 publications

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“…An alternative explanation for this interesting phenomenon is that the Nrf2-ARE pathway is activated by silibinin's metabolites, rather than silibinin itself. As TAMH is metabolically active [83], it may convert silibinin to metabolites that structurally resemble the analogue 2,3-dehydrosilydianin, which has been reported to upregulate NQO1 activity [46]. The differences between our results and previous findings [46,65] may thus be attributed to innate metabolic, transporter-related, and physiological differences between various cell lines.…”

Section: Discussioncontrasting

confidence: 67%

An Evaluation of the In Vitro Roles and Mechanisms of Silibinin in Reducing Pyrazinamide- and Isoniazid-Induced Hepatocellular Damage

Goh

Tee

2020

IJMS

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Tuberculosis remains a significant infectious lung disease that affects millions of patients worldwide. Despite numerous existing drug regimens for tuberculosis, drug-induced liver injury is a major challenge that limits the effectiveness of these therapeutics. Two drugs that form the backbone of the commonly administered quadruple antitubercular regimen, that is, pyrazinamide (PZA) and isoniazid (INH), are associated with such hepatotoxicity. Yet, we lack safe and effective alternatives to the antitubercular regimen. Consequently, current research largely focuses on exploiting the hepatoprotective effect of nutraceutical compounds as complementary therapy. Silibinin, a herbal product widely believed to protect against various liver diseases, potentially provides a useful solution given its hepatoprotective mechanisms. In our study, we identified silibinin’s role in mitigating PZA- and INH-induced hepatotoxicity and elucidated a deeper mechanistic understanding of silibinin’s hepatoprotective ability. Silibinin preserved the viability of human foetal hepatocyte line LO2 when co-administered with 80 mM INH and decreased apoptosis induced by a combination of 40 mM INH and 10 mM PZA by reducing oxidative damage to mitochondria, proteins, and lipids. Taken together, this proof-of-concept forms the rational basis for the further investigation of silibinin’s hepatoprotective effect in subsequent preclinical studies and clinical trials.

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Section: Discussioncontrasting

confidence: 67%

An Evaluation of the In Vitro Roles and Mechanisms of Silibinin in Reducing Pyrazinamide- and Isoniazid-Induced Hepatocellular Damage

Goh

Tee

2020

IJMS

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“…While TAMH is of mouse species origin, it is chosen for its comparable cytochrome P450 enzyme expressions with wild-type liver or primary mouse hepatocytes, which renders it desirable for the study of AILI where toxicity arises from the accumulation of its active metabolite, NAPQI. 34,35 In fact, it has been frequently reported as a cell model for studying AILI and it displayed distinct features of APAP toxicity. 36,37 Furthermore, to ensure translatability of results beyond mouse species, hypothermic effects were once again examined in human hepatocyte model, L-02.…”

Section: Discussionmentioning

confidence: 99%

Moderate Hypothermia Effectively Alleviates Acetaminophen-Induced Liver Injury With Prolonged Action Beyond Cooling

Tan

Tey

2020

Dose-Response

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Acetaminophen (APAP) overdose accounts for the highest incidence of acute liver failure, despite the availability of an antidote i.e. N-acetylcysteine. This calls for alternative strategies to manage APAP-induced liver injury (AILI). Therapeutic hypothermia has been explored in past studies for hepatoprotection, but these phenomenal reports lack clarification of its optimal window for application, and mechanistic effects in specific AILI. Hence, we conducted an in vitro study with transforming growth factor-α transgenic mouse hepatocytes cell line, TAMH, and human liver hepatocytes cell line, L-02, where cells were conditioned with deep (25°C) or moderate (32°C) hypothermia before, during or after APAP toxicity. Cell viability was evaluated as a hallmark of cytoprotection, along with cell death. Simultaneously, cold shock proteins (CSPs) and heat shock proteins expressions were monitored; key liver functions including drug-metabolizing ability and hepatic clearance were also investigated. Herein, we demonstrated significant hepatoprotection with 24-hour moderate hypothermic conditioning during AILI and this effect sustained for at least 24 hours of rewarming. Such liver preservation was associated with a CSP—RNA-binding motif protein 3 (RBM3) as its knockdown promptly abolished the cytoprotective effects of hypothermia. With mild and reversible liver perturbations, hypothermic therapy appears promising and its RBM3 involvement deserves future exploration.

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“…Protein binding leads to oxidative stress and mitochondrial damage ( McGill and Jaeschke, 2013 ; Caparrotta et al, 2018 ). Paracetamol toxicity is also related to calcium accumulation and activation of endonucleases, DNA damage ( Boelsterli, 2003 ), ATP depletion, Jnk activation, up-regulation of electron transport chain protein components and activation of p53 signaling ( Davis and Stamper, 2016 ).…”

Section: Liver In Vitro Models For Toxicological Smentioning

confidence: 99%

A Critical Perspective on 3D Liver Models for Drug Metabolism and Toxicology Studies

Serras

Rodrigues

Cipriano

et al. 2021

Front. Cell Dev. Biol.

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The poor predictability of human liver toxicity is still causing high attrition rates of drug candidates in the pharmaceutical industry at the non-clinical, clinical, and post-marketing authorization stages. This is in part caused by animal models that fail to predict various human adverse drug reactions (ADRs), resulting in undetected hepatotoxicity at the non-clinical phase of drug development. In an effort to increase the prediction of human hepatotoxicity, different approaches to enhance the physiological relevance of hepatic in vitro systems are being pursued. Three-dimensional (3D) or microfluidic technologies allow to better recapitulate hepatocyte organization and cell-matrix contacts, to include additional cell types, to incorporate fluid flow and to create gradients of oxygen and nutrients, which have led to improved differentiated cell phenotype and functionality. This comprehensive review addresses the drug-induced hepatotoxicity mechanisms and the currently available 3D liver in vitro models, their characteristics, as well as their advantages and limitations for human hepatotoxicity assessment. In addition, since toxic responses are greatly dependent on the culture model, a comparative analysis of the toxicity studies performed using two-dimensional (2D) and 3D in vitro strategies with recognized hepatotoxic compounds, such as paracetamol, diclofenac, and troglitazone is performed, further highlighting the need for harmonization of the respective characterization methods. Finally, taking a step forward, we propose a roadmap for the assessment of drugs hepatotoxicity based on fully characterized fit-for-purpose in vitro models, taking advantage of the best of each model, which will ultimately contribute to more informed decision-making in the drug development and risk assessment fields.

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TAMH: A Useful In Vitro Model for Assessing Hepatotoxic Mechanisms

Cited by 15 publications

References 75 publications

An Evaluation of the In Vitro Roles and Mechanisms of Silibinin in Reducing Pyrazinamide- and Isoniazid-Induced Hepatocellular Damage

An Evaluation of the In Vitro Roles and Mechanisms of Silibinin in Reducing Pyrazinamide- and Isoniazid-Induced Hepatocellular Damage

Moderate Hypothermia Effectively Alleviates Acetaminophen-Induced Liver Injury With Prolonged Action Beyond Cooling

A Critical Perspective on 3D Liver Models for Drug Metabolism and Toxicology Studies

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