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Pharmacogene expression during progression of metabolic dysfunction-associated steatotic liver disease: Studies on mRNA and protein levels and their relevance to drug treatment

Lookup NU author(s): Dr Olivier Govaere, Dr Simon CockellORCiD, Michalina Zatorska, Kristy Wonders, Professor Dina Tiniakos, Dr Andrew FreyORCiD, Dr Pawel PalmowskiORCiD, Ruth Walker, Dr Andrew Porter, Professor Matthias TrostORCiD, Professor Quentin AnsteeORCiD, Professor Ann DalyORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2024. Metabolic dysfunction-associated steatotic liver disease (MASLD) is common worldwide. Genes and proteins contributing to drug disposition may show altered expression as MASLD progresses. To assess this further, we undertook transcriptomic and proteomic analysis of 137 pharmacogenes in liver biopsies from a large MASLD cohort. We performed sequencing on RNA from 216 liver biopsies (206 MASLD and 10 controls). Untargeted mass spectrometry proteomics was performed on a 103 biopsy subgroup. Selected RNA sequencing signals were replicated with an additional 187 biopsies. Comparison of advanced MASLD (fibrosis score 3/4) with milder disease (fibrosis score 0–2) by RNA sequencing showed significant alterations in expression of certain phase I, phase II and ABC transporters. For cytochromes P450, CYP2C19 showed the most significant decreased expression (30 % of that in mild disease) but significant decreased expression of other CYPs (including CYP2C8 and CYP2E1) also occurred. CYP2C19 also showed a significant decrease comparing the inflammatory form of MASLD (MASH) with non-MASH biopsies. Findings for CYP2C19 were confirmed in the replication cohort. Proteomics on the original discovery cohort confirmed decreased levels of several CYPs as MASLD advanced but this decrease was greatest for CYP2C19 where levels fell to 40 % control. This decrease may result in decreased CYP2C19 activity that could be problematic for prescription of drugs activated or metabolized by CYP2C19 as MASLD advances. More limited decreases for other P450s suggest fewer issues with non-CYP2C19 drug substrates. Negative correlations at RNA level between CYP2C19 and several cytokine genes provided initial insights into the mechanism underlying decreased expression.

Publication metadata

Author(s): Govaere O, Cockell SJ, Zatorska M, Wonders K, Tiniakos D, Frey AM, Palmowksi P, Walker R, Porter A, Trost M, Anstee QM, Daly AK

Publication type: Article

Publication status: Published

Journal: Biochemical Pharmacology

Year: 2024

Pages: ePub ahead of Print

Online publication date: 30/04/2024

Acceptance date: 29/04/2024

Date deposited: 15/05/2024

ISSN (print): 0006-2952

ISSN (electronic): 1873-2968

Publisher: Elsevier Inc.


DOI: 10.1016/j.bcp.2024.116249

PubMed id: 38697308


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Funder referenceFunder name
European Union Horizon 2020