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Albert Braeuning, Michael Schwarz. Regulation of expression of drug-metabolizing enzymes by oncogenic signaling pathways in liver tumors: a review[J]. Acta Pharmaceutica Sinica B, 2020, 10(1): 113-122

Regulation of expression of drug-metabolizing enzymes by oncogenic signaling pathways in liver tumors: a review
Albert Braeuninga, Michael Schwarzb
a German Federal Institute for Risk Assessment, Dept. Food Safety, Berlin 10589, Germany;
b Eberhard Karls University of Tübingen, Inst. of Pharmacology and Toxicology, Dept. of Toxicology, Tübingen 72074, Germany
Abstract:
Mutations in genes encoding key players in oncogenic signaling pathways trigger specific downstream gene expression profiles in the respective tumor cell populations. While regulation of genes related to cell growth, survival, and death has been extensively studied, much less is known on the regulation of drug-metabolizing enzymes (DMEs) by oncogenic signaling. Here, a comprehensive review of the available literature is presented summarizing the impact of the most relevant genetic alterations in human and rodent liver tumors on the expression of DMEs with a focus on phases I and II of xenobiotic metabolism. Comparably few data are available with respect to DME regulation by p53-dependent signaling, telomerase expression or altered chromatin remodeling. By contrast, DME regulation by constitutive activation of oncogenic signaling via the RAS/RAF/mitogen-activated protein kinase (MAPK) cascade or via the canonical WNT/β-catenin signaling pathway has been analyzed in greater depth, demonstrating mostly positive-regulatory effects of WNT/β-catenin signaling and negativeregulatory effects of MAPK signaling. Mechanistic studies have revealed molecular interactions between oncogenic signaling and nuclear xeno-sensing receptors which underlie the observed alterations in DME expression in liver tumors. Observations of altered DME expression and inducibility in liver tumors with a specific gene expression profile may impact pharmacological treatment options.
Key words:    Xenobiotic metabolism    Hepatocytes    WNT/β-catenin signaling    RAS/MAPK signaling    Gene mutation    Cytochrome P450   
Received: 2019-03-21     Revised: 2019-05-23
DOI: 10.1016/j.apsb.2019.06.013
Corresponding author: Michael Schwarz     Email:michael.schwarz@uni-tuebingen.de
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Albert Braeuning
Michael Schwarz

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