HepaRG Cells Adopt Zonal-Like Drug-Metabolizing Phenotypes under Physiologically Relevant Oxygen Tensions and Wnt/β-Catenin Signaling

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外文摘要：The cellular microenvironment plays an important role in liver zo-nation, the spatial distribution of metabolic tasks among hepato-cytes lining the sinusoid. Standard tissue culture practices provide an excess of oxygen and a lack of signaling molecules typically found in the liver. We hypothesized that incorporating physiologically relevant environments would promote postdifferentiation patterning of hepatocytes and result in zonal-like characteristics. To test this hypothesis, we evaluated the transcriptional regulation and activity of drug-metabolizing enzymes in HepaRG cells exposed to three different oxygen tensions, in the presence or absence of Wnt/b-catenin signaling. The drug-metabolizing activity of cells exposed to representative periportal (11% O_2) or perivenous (5% O_2) oxygen tensions were significantly less than cells exposed to ambient oxygen. A comparison of cytochrome P450 (P450) 1A2, 2D6, and 3A4 activity at periportal and perivenous oxygen tensions showed significant increases at the lower oxygen tension. The activation of the Wnt/β-catenin pathway only modestly impacted P450 activity at perivenous oxygen tension, despite a significant increase in P450 expression under this condition. Our results suggest oxygen tension is the major contributor to zonal patterning in HepaRG cells, with the Wnt/β-catenin signaling pathway playing a lesser albeit important role. Our datasets also highlight the importance of including activity-based assays, as transcript data alone do not provide an accurate picture of metabolic competence.

作者：

Thomas J. DiProspero、Lauren G. Brown、Trevor D. Fachko、Matthew R. Lockett

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作者单位：

Department of Chemistry, Kenan and Caudill Laboratories, University of North Carolina at Chapel

出版年：

2022

Drug Metabolism and Disposition

SCI

ISSN：0090-9556

年,卷(期)：2022.50(8)