Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 19 (10), 830-838

Models of Drug Induced Liver Injury (DILI) - Current Issues and Future Perspectives

Affiliations
Review

Models of Drug Induced Liver Injury (DILI) - Current Issues and Future Perspectives

Lucija Kuna et al. Curr Drug Metab.

Abstract

Background: Drug-induced Liver Injury (DILI) is an important cause of acute liver failure cases in the United States, and remains a common cause of withdrawal of drugs in both preclinical and clinical phases.

Methods: A structured search of bibliographic databases - Web of Science Core Collection, Scopus and Medline for peer-reviewed articles on models of DILI was performed. The reference lists of relevant studies was prepared and a citation search for the included studies was carried out. In addition, the characteristics of screened studies were described.

Results: One hundred and six articles about the existing knowledge of appropriate models to study DILI in vitro and in vivo with special focus on hepatic cell models, variations of 3D co-cultures, animal models, databases and predictive modeling and translational biomarkers developed to understand the mechanisms and pathophysiology of DILI are described.

Conclusion: Besides descriptions of current applications of existing modeling systems, associated advantages and limitations of each modeling system and future directions for research development are discussed as well.

Keywords: Drug evaluation studies; drug-induced; evidence-based toxicology; liver injury; preclinical; side effects..

Figures

Fig. (1)
Fig. (1)
Division of DILI types based on dose dependency and immune response.
Fig. (2)
Fig. (2)
Algorithm of Acetaminophen toxicity in liver. Acetaminophen (APAP) impairs mitochondrial function by the creation of a reactive metabolite N-acetyl-p-benzoquinone Imine (NAPQI), which is induced mostly by the cytochrome P450 enzymes, resulting in depletion of mitochondrial Glutathione (GSH). Once glutathione is depleted, NAPQI binds to subcellular organelles in the cell, causing the binding of APAP to cellular proteins resulting in disruption of calcium homeostasis, mitochondrial dysfunction, oxidative stress, collapses ATP production and may culminate in cell necrosis and death.
Fig. (3)
Fig. (3)
Algorithm of liver damage in allergic and non-allergic DILI models. In the allergic DILI model, drugs or reactive metabolites bind to host proteins (haptenization), and hapten-peptides are processed and represented on HLA binding gutter of antigen-presenting cells (APC) by CD4 T-cells. In non-allergic DILI model drugs or reactive metabolites gradually accumulate in hepatocytes and directly stress mitochondria, enhancing mitochondrial Reactive Oxygen Species (ROS) production. Toxic and metabolic stress activates signal transduction pathways resulting in alterations in mitochondrial. Injured mitochondria relief different contents, as mtDNA and activate cytokines inducing apoptosis or necrosis.
Fig. (4)
Fig. (4)
Schematic presentation of possible data sources used for development of predictive models for DILI models. There are two basic groups; predictive models from homogenous data and from heterogeneous data. The first group is subdivided into three categories: chemical structure-based in silico (or computational) model, in vitro assay-based models and toxicogenomics-based models. The second group is subdivided into two categories: the first category is data integration-based models which use multiple sources of data for developing one predictive model. The second category - model integration uses multiple individually developed models from multiple data sources.

Similar articles

See all similar articles

References

    1. Hamilton L.A., Collins-Yoder A., Collins R.E. Drug-induced liver injury. AACN Adv. Crit. Care. 2016;27(4):430–440. - PubMed
    1. Vuppalanchi R., Liangpunsakul S., Chalasani N. Etiology of new-onset jaundice: how often is it caused by idiosyncratic drug-induced liver injury in the United States? Am. J. Gastroenterol. 2007;102(3):558–562. - PubMed
    1. Reuben A., Koch D.G., Lee W.M., Group A.L.F.S. Drug-induced acute liver failure: Results of a U.S. multicenter, prospective study. Hepatology. 2010;52(6):2065–2076. - PMC - PubMed
    1. Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat. Rev. Drug Discov. 2005;4(6):489–499. - PubMed
    1. Ostapowicz G., Fontana R.J., Schiødt F.V., Larson A., Davern T.J., Han S.H., McCashland T.M., Shakil A.O., Hay J.E., Hynan L., Crippin J.S., Blei A.T., Samuel G., Reisch J., Lee W.M., U.S. Acute Liver Failure Study Group Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann. Intern. Med. 2002;137(12):947–954. - PubMed
Feedback