Characterization of primary mouse hepatocyte spheroids as a model system to support investigations of drug-induced liver injury

Transcriptional factor NRF2 is an emerging tool in reviewing mechanistic behavior of drug-specific injury pathways. Drug-induced liver injury (DILI) represents a major clinical concern that often manifests oxidative stress and cell death. Despite the pivotal role of NRF2 pathway in liver pathologies, it is questioned whether NRF2 activation or regulatory efficiency could be hindered in by the severity of DILI and progression of cell death. In this study, we evaluate NRF2 as a biomarker to DILI in comparison to severity of injury as well as explore stress mediating factors affecting Nrf2 expression. In vivo DILI model was established in C57BL/6 mice by acetaminophen (APAP) at different toxic doses, confirmed by dose-dependent liver pathological changes and accompanied with in vitro time- and dose-dependent depletion of GSH and SOD in isolated primary mouse hepatocytes. Increase in liver NRF2 translocation and cytosolic content was observed in 70 mg/kg APAP-treated mice. At this subtoxic dose, liver Nrf2 transcription was increased in mice by 18.3-fold, a prominent downregulation was seen in ARE (antioxidant response element) genes; Hmox1, Nqo1 and Glcm, and apoptotic Bcl2 regulating genes. In addition, upregulation in necrosis inducer Parp2 was associated to downregulation in Hmgb1. Collectively, expression of genes related to cell survival were regulated at mild APAP hepatotoxicity. By increasing APAP dose, hemorrhagic necrosis and impaired genetic transcription in both Nrf2 and several other genes were evident. In conclusion, NRF2/ARE system and cell death modulation is halted by the increase of chemical stress and found directly associated with DILI severity.

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Phenotypic characterization of idiosyncratic drug-induced liver injury: The influence of age and sex

Hepatology ◽

10.1002/hep.22895 ◽

2009 ◽

Vol 49 (6) ◽

pp. 2001-2009 ◽

Cited By ~ 192

Author(s):

M. Isabel Lucena ◽

Raúl J. Andrade ◽

Neil Kaplowitz ◽

Miren García-Cortes ◽

M. Carmen Fernández ◽

...

Keyword(s):

Liver Injury ◽

Phenotypic Characterization ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Age And Sex

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Transcriptional, Functional, and Mechanistic Comparisons of Stem Cell–Derived Hepatocytes, HepaRG Cells, and Three-Dimensional Human Hepatocyte Spheroids as Predictive In Vitro Systems for Drug-Induced Liver Injury

Drug Metabolism and Disposition ◽

10.1124/dmd.116.074369 ◽

2017 ◽

Vol 45 (4) ◽

pp. 419-429 ◽

Cited By ~ 71

Author(s):

Catherine C. Bell ◽

Volker M. Lauschke ◽

Sabine U. Vorrink ◽

Henrik Palmgren ◽

Rodger Duffin ◽

...

Keyword(s):

Stem Cell ◽

Liver Injury ◽

Three Dimensional ◽

Human Hepatocyte ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Heparg Cells ◽

In Vitro Systems ◽

Hepatocyte Spheroids

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Critical Review of Gaps in the Diagnosis and Management of Drug-Induced Liver Injury Associated with Severe Cutaneous Adverse Reactions

Journal of Clinical Medicine ◽

10.3390/jcm10225317 ◽

2021 ◽

Vol 10 (22) ◽

pp. 5317

Author(s):

Marina Villanueva-Paz ◽

Hao Niu ◽

Antonio Segovia-Zafra ◽

Inmaculada Medina-Caliz ◽

Judith Sanabria-Cabrera ◽

...

Keyword(s):

Liver Injury ◽

Adverse Reactions ◽

Randomized Clinical Trials ◽

Skin Injury ◽

Drug Induced ◽

Cutaneous Manifestations ◽

Drug Induced Liver Injury ◽

Complex Disorder ◽

Cutaneous Adverse Reactions

Drug-induced liver injury (DILI) encompasses the unexpected damage that drugs can cause to the liver. DILI may develop in the context of an immunoallergic syndrome with cutaneous manifestations, which are sometimes severe (SCARs). Nevirapine, allopurinol, anti-epileptics, sulfonamides, and antibiotics are the most frequent culprit drugs for DILI associated with SCARs. Interestingly, alleles HLA-B*58:01 and HLA-A*31:01 are associated with both adverse reactions. However, there is no consensus about the criteria used for the characterization of liver injury in this context, and the different thresholds for DILI definition make it difficult to gain insight into this complex disorder. Moreover, current limitations when evaluating causality in patients with DILI associated with SCARs are related to the plethora of causality assessment methods and the lack of consensual complementary tools. Finally, the management of this condition encompasses the treatment of liver and skin injury. Although the use of immunomodulant agents is accepted for SCARs, their role in treating liver injury remains controversial. Further randomized clinical trials are needed to test their efficacy and safety to address this complex entity. Therefore, this review aims to identify the current gaps in the definition, diagnosis, prognosis, and management of DILI associated with SCARs, proposing different strategies to fill in these gaps.

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