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Korver S, Bowen J, Pearson K, et al. The application of cytokeratin-18 as a biomarker for drug-induced liver injury. Arch Toxicol. 2021;95(11):3435-3448doi: 10.1007/s00204-021-03121-0.
Korver, S., Bowen, J., Pearson, K., Gonzalez, R. J., French, N., Park, K., Jenkins, R., & Goldring, C. (2021). The application of cytokeratin-18 as a biomarker for drug-induced liver injury. Archives of toxicology, 95(11), 3435-3448. https://doi.org/10.1007/s00204-021-03121-0
Korver, Samantha, et al. "The application of cytokeratin-18 as a biomarker for drug-induced liver injury." Archives of toxicology vol. 95,11 (2021): 3435-3448. doi: https://doi.org/10.1007/s00204-021-03121-0
Korver S, Bowen J, Pearson K, Gonzalez RJ, French N, Park K, Jenkins R, Goldring C. The application of cytokeratin-18 as a biomarker for drug-induced liver injury. Arch Toxicol. 2021 Nov;95(11):3435-3448. doi: 10.1007/s00204-021-03121-0. Epub 2021 Jul 29. PMID: 34322741; PMCID: PMC8492595.
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Arch Toxicol. 2021 Nov;95(11):3435-3448. doi: 10.1007/s00204-021-03121-0. Epub 2021 Jul 29.

The application of cytokeratin-18 as a biomarker for drug-induced liver injury.

Archives of toxicology

Samantha Korver, Joanne Bowen, Kara Pearson, Raymond J Gonzalez, Neil French, Kevin Park, Rosalind Jenkins, Christopher Goldring

Affiliations

  1. Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK. [email protected].
  2. Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia. [email protected].
  3. Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia.
  4. Merck and Co. Inc, Kenilworth, NJ, USA.
  5. Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.

PMID: 34322741 PMCID: PMC8492595 DOI: 10.1007/s00204-021-03121-0

Abstract

Drug-induced liver injury (DILI) is a frequent and dangerous adverse effect faced during preclinical and clinical drug therapy. DILI is a leading cause of candidate drug attrition, withdrawal and in clinic, is the primary cause of acute liver failure. Traditional diagnostic markers for DILI include alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). Yet, these routinely used diagnostic markers have several noteworthy limitations, restricting their sensitivity, specificity and accuracy in diagnosing DILI. Consequently, new biomarkers for DILI need to be identified.A potential biomarker for DILI is cytokeratin-18 (CK18), an intermediate filament protein highly abundant in hepatocytes and cholangiocytes. Extensively researched in a variety of clinical settings, both full length and cleaved forms of CK18 can diagnose early-stage DILI and provide insight into the mechanism of hepatocellular injury compared to traditionally used diagnostic markers. However, relatively little research has been conducted on CK18 in preclinical models of DILI. In particular, CK18 and its relationship with DILI is yet to be characterised in an in vivo rat model. Such characterization of CK18 and ccCK18 responses may enable their use as translational biomarkers for hepatotoxicity and facilitate management of clinical DILI risk in drug development. The aim of this review is to discuss the application of CK18 as a biomarker for DILI. Specifically, this review will highlight the properties of CK18, summarise clinical research that utilised CK18 to diagnose DILI and examine the current challenges preventing the characterisation of CK18 in an in vivo rat model of DILI.

© 2021. The Author(s).

Keywords: Biomarker; Cytokeratin-18 (CK18); Drug-induced liver injury (DILI); Hepatotoxicity; In vivo

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