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The Wnt/β-catenin signaling pathway plays a role in drug-induced liver injury by regulating cytochrome P450 2E1 expression

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Abstract

Drug-induced liver injury (DILI) is a major cause of acute liver failure and drug withdrawal. Cytochrome P450 (CYP) 2E1 is involved in the metabolism of several drugs, and can induce liver injury through the production of toxic metabolites and the generation of reactive oxygen species. This study aimed to elucidate the role of Wnt/β-catenin signaling in CYP2E1 regulation for drug-induced hepatotoxicity. To achieve this, mice were administered cisplatin or acetaminophen (APAP) 1 h after treatment with the CYP2E1 inhibitor dimethyl sulfoxide (DMSO), and histopathological and serum biochemical analyses were performed. APAP treatment induced hepatotoxicity, as evidenced by an increase in liver weight and serum ALT levels. Moreover, histological analysis indicated severe injury, including apoptosis, in the liver tissue of APAP-treated mice, which was confirmed by TUNEL assay. Additionally, APAP treatment suppressed the antioxidant capacity of the mice and increased the expression of the DNA damage markers γ-H2AX and p53. However, these effects of APAP on hepatotoxicity were significantly attenuated by DMSO treatment. Furthermore, the activation of Wnt/β-catenin signaling using the Wnt agonist CHIR99021 (CHIR) increased CYP2E1 expression in rat liver epithelial cells (WB-F344), whereas treatment with the Wnt/β-catenin antagonist IWP-2 inhibited nuclear β-catenin and CYP2E1 expression. Interestingly, APAP-induced cytotoxicity in WB-F344 cells was exacerbated by CHIR treatment and suppressed by IWP-2 treatment. Overall, these results showed that the Wnt/β-catenin signaling is involved in DILI through the upregulation of CYP2E1 expression by directly binding the transcription factor β-cat/TCF to the Cyp2e1 promoter, thus exacerbating DILI.

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Data Availability

Data generated and/or analyzed during the current study are available from the corresponding authors upon reasonable request.

Abbreviations

ALT:

alanine aminotransferase

ALF:

acute liver failure

APAP:

acetaminophen

AST:

aspartate aminotransferase

ChIP:

chromatin immunoprecipitation

CHIR:

CHIR99021

CYP:

Cytochrome P450

DILI:

Drug-Induced Liver Injury

DMSO:

dimethyl sulfoxide

GSH:

glutathione

GPX:

glutathione peroxidase

H&E:

hematoxylin and eosin

HSCs:

hepatic stellate cells

LEF:

lymphoid enhancer factor

LRP-5/6:

lipoprotein receptor-related proteins 5 and 6

NAPQI:

N-acetyl-p-benzoquinone imine

PBST:

phosphate-buffered saline with 0.1% Tween ® 20 detergent Pt platinum

ROS:

reactive oxygen species

SOD1:

superoxide dismutase 1

TBS:

tris-buffered saline

TCF:

T-cell factor

TUNEL:

terminal deoxynucleotidyl transferase dUTP nick end labeling

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Acknowledgements

We thank Seoul National University Hospital (Seoul, Korea) for providing WB-F344 cells.

Funding

This work was supported by the Basic Science Research Program (2021R1A2C1009563) through the National Research Foundation (NRF) of Korea, funded by the Ministry of Science and ICT (MSIT), Republic of Korea.

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Authors and Affiliations

  1. Department of Research and Development, SML Genetree, Seoul, 05855, Republic of Korea

    Yoo-Sub Shin

  2. Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662, Republic of Korea

    Yoo-Sub Shin, Da-Bin Hwang, Dong-Hoon Won, Shin-Young Kim & Changuk Kim

  3. Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, 24341, Republic of Korea

    Jun Won Park

  4. Laboratory of Veterinary Toxicology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea

    Young Jeon & Jun-Won Yun

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Contributions

All authors contributed to the study conception and design. Material preparation and data collection were performed by YSS, DBH, DHW, SYK, and CK. Data analysis were performed by YSS, DBH, JWP, YJ, and JWY. The first draft of the manuscript was written by YSS and DBH. And, writing-review, editing and supervision were performed by JWY. All authors read and approved the final manuscript.

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Correspondence to Jun-Won Yun.

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All animal experimental procedures were performed after approval by the Institutional Animal Care and Use Committee at The Catholic University of Korea.

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Shin, YS., Hwang, DB., Won, DH. et al. The Wnt/β-catenin signaling pathway plays a role in drug-induced liver injury by regulating cytochrome P450 2E1 expression. Toxicol Res. 39, 443–453 (2023). https://doi.org/10.1007/s43188-023-00180-6

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