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Article

Phenobarbital Induces SLC13A5 Expression through Activation of PXR but Not CAR in Human Primary Hepatocytes

1
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA
2
BioIVT, 1450 S Rolling Road, Halethorpe, MD 21227, USA
3
Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
4
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
*
Author to whom correspondence should be addressed.
Cells 2021, 10(12), 3381; https://doi.org/10.3390/cells10123381
Submission received: 15 November 2021 / Revised: 26 November 2021 / Accepted: 29 November 2021 / Published: 1 December 2021

Abstract

Phenobarbital (PB), a widely used antiepileptic drug, is known to upregulate the expression of numerous drug-metabolizing enzymes and transporters in the liver primarily via activation of the constitutive androstane receptor (CAR, NR1I3). The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter, plays an important role in intracellular citrate homeostasis that is associated with a number of metabolic syndromes and neurological disorders. Here, we show that PB markedly elevates the expression of SLC13A5 through a pregnane X receptor (PXR)-dependent but CAR-independent signaling pathway. In human primary hepatocytes, the mRNA and protein expression of SLC13A5 was robustly induced by PB treatment, while genetic knockdown or pharmacological inhibition of PXR significantly attenuated this induction. Utilizing genetically modified HepaRG cells, we found that PB induces SLC13A5 expression in both wild type and CAR-knockout HepaRG cells, whereas such induction was fully abolished in the PXR-knockout HepaRG cells. Mechanistically, we identified and functionally characterized three enhancer modules located upstream from the transcription start site or introns of the SLC13A5 gene that are associated with the regulation of PXR-mediated SLC13A5 induction. Moreover, metformin, a deactivator of PXR, dramatically suppressed PB-mediated induction of hepatic SLC13A5 as well as its activation of the SLC13A5 luciferase reporter activity via PXR. Collectively, these data reveal PB as a potent inducer of SLC13A5 through the activation of PXR but not CAR in human primary hepatocytes.
Keywords: phenobarbital; SLC13A5; PXR; CAR phenobarbital; SLC13A5; PXR; CAR

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MDPI and ACS Style

Li, Z.; Li, L.; Heyward, S.; Men, S.; Xu, M.; Sueyoshi, T.; Wang, H. Phenobarbital Induces SLC13A5 Expression through Activation of PXR but Not CAR in Human Primary Hepatocytes. Cells 2021, 10, 3381. https://doi.org/10.3390/cells10123381

AMA Style

Li Z, Li L, Heyward S, Men S, Xu M, Sueyoshi T, Wang H. Phenobarbital Induces SLC13A5 Expression through Activation of PXR but Not CAR in Human Primary Hepatocytes. Cells. 2021; 10(12):3381. https://doi.org/10.3390/cells10123381

Chicago/Turabian Style

Li, Zhihui, Linhao Li, Scott Heyward, Shuaiqian Men, Meishu Xu, Tatsuya Sueyoshi, and Hongbing Wang. 2021. "Phenobarbital Induces SLC13A5 Expression through Activation of PXR but Not CAR in Human Primary Hepatocytes" Cells 10, no. 12: 3381. https://doi.org/10.3390/cells10123381

APA Style

Li, Z., Li, L., Heyward, S., Men, S., Xu, M., Sueyoshi, T., & Wang, H. (2021). Phenobarbital Induces SLC13A5 Expression through Activation of PXR but Not CAR in Human Primary Hepatocytes. Cells, 10(12), 3381. https://doi.org/10.3390/cells10123381

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