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Transcriptional profiling of drug-induced liver injury biomarkers: association of hepatic Srebf1/Pparα signaling and crosstalk of thrombin, alcohol dehydrogenase, MDR and DNA damage regulators

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Abstract

Cell stress transcribing genes provide a diverse platform of molecular mediators that vary in response to toxicity. Common drug-induced liver injury (DILI) biomarkers are usually expressed in mild toxicity and limited to confirming it rather than categorizing its intensity. Thus, new parametric biomarkers are needed to be explored. Classifying the toxicological response based on the dose-level and severity of stimuli will aid in the evaluation and approach against drug exposure. The present research explored the involvement of gene expression of potential biomarkers as a severity-specific hallmark in different acetaminophen (APAP)-induced hepatotoxicity levels in C57BL/6 mice. The differentially expressed genes were annotated and analyzed using bioinformatics tools to predict canonical pathways altered by DILI. The results revealed alteration in genes encoding for antioxidant enhancement; Slc7a11, bile efflux; MDR4, fatty acid metabolism and transcriptional factors namely Srebf1 and Pparα. Potential APAP toxicity biomarkers included Adh1 and thrombin, and other DNA damage and stress chaperones which were changed at least fourfold between control and the three tested severity models. The current investigation demonstrates a dose-mediated association of several hallmark genes in APAP-induced liver damage and addressed the involvement of uncommonly studied molecular responses. Such biomarkers can be further developed into predictive models, translated for risk assessment against drug exposure and guide in building theragnostic targets.

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The datasets generated and/or analyzed during the current study are available at request from the corresponding author.

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Acknowledgements

This study was supported by grant (11/4/2019) from the Deanship of Scientific Research, University of Petra, Amman, Jordan.

Funding

This study was funded by the Deanship of Scientific Research, University of Petra, Amman, Jordan (Grant Number 11/4/2019).

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Authors and Affiliations

  1. University of Petra Pharmaceutical Center (UPPC), Faculty of Pharmacy and Medical Sciences, University of Petra, P.O. Box 961343, Amman, 11196, Jordan

    Bayan Y. Ghanim, Qasem Abdallah & Nidal A. Qinna

  2. Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4099-002, Porto, Portugal

    Mohammad Ahmad

  3. Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, 11196, Jordan

    Qasem Abdallah, Anas Khaleel & Nidal A. Qinna

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  1. Bayan Y. Ghanim
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Contributions

Authors' contributions: Conceptualization: BYG, NAQ; Methodology: BYG, MIA, NAQ; Formal analysis and investigation: BYG, AK, QMA, NAQ; Writing—original draft preparation: BYG; Writing—review and editing: BYG, AK, QMA, NAQ; Funding acquisition: NAQ; Resources: NAQ; Supervision: NAQ. All authors read and approved the final manuscript.

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Correspondence to Nidal A. Qinna.

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Ghanim, B.Y., Ahmad, M., Abdallah, Q. et al. Transcriptional profiling of drug-induced liver injury biomarkers: association of hepatic Srebf1/Pparα signaling and crosstalk of thrombin, alcohol dehydrogenase, MDR and DNA damage regulators. Mol Cell Biochem 478, 1949–1960 (2023). https://doi.org/10.1007/s11010-022-04648-1

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