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Research ArticleOpen Access

Roles of the Nuclear Receptors PXR1 and PXR2 in the Regulation of Cytochrome P450 3A11 Expression in Mouse Organs and Primary-Cultured Hepatocytes

Volume 5 - Issue 3

Wataru Ochiai*1, Ryosuke Miki2, Mari Fukuda1, Haruka Kato1, Yuya Nakajo1, Ryuki Iimura1, Jo Hatogai1, Shohei Harada1, Satoshi Kitaoka1, and Kiyoshi Sugiyama2

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    • 1Department of Clinical Pharmacokinetics, Hoshi University, Japan
    • 2Department of Functional Molecule Kinetics Hoshi University, Japan

    *Corresponding author: Wataru Ochiai, Department of Clinical Pharmacokinetics, Hoshi University, Japan

Received: June 03, 2018;   Published: June 12, 2018

DOI: 10.26717/BJSTR.2018.05.001206

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Abstract

Pregnane X receptor (PXR) is a nuclear receptor that exists in forms such as PXR1 and PXR2. Activated PXR1 heterodimerizes with retinoid X receptor to increase the transcription of cytochrome P450 3A (CYP3A), a drug-metabolizing enzyme, by binding to the PXR biding site in nuclei. PXR2 is a splice variant of PXR1, which is localized to the nuclei and down regulates the transcription of CYP3A by PXR1. The present study investigated the roles of PXR1 and PXR2 in the regulation of CYP3A11 expression in adult mouse organs and primary cultured hepatocytes. In the liver and small intestine, which show high expression of CYP3A11 mRNA, PXR1 mRNA was highly expressed while PXR2 mRNA expression was low. In the lung, kidneys, heart, and stomach, which show low expression of CYP3A11 mRNA, both PXR1 and PXR2 mRNA were expressed at high levels. In the muscle and spleen, which express little CYP3A11 mRNA, both PXR1 and PXR2 mRNA were expressed at low levels. In primary-cultured hepatocytes, PXR1 mRNA was expressed at high levels on day 0 of culture, and markedly decreased beginning on day 1. PXR2 mRNA was expressed at low levels on day 0, and gradually increased until day 5. CYP3A11 mRNA exhibited a different expression pattern from that of PXR1 or PXR2; expression peaked on day 0 and then gradually decreased. These results suggest that CYP3A11 expression is upregulated by PXR1 and downregulated by PXR2.

Keywords: PXR1; PXR2; CYP3A11; Hepatocyte; Liver

Abbreviations: VDR: Vitamin D receptor; PXR: Pregnane X Receptor; CAR: Constitutive Androstane Receptor; RXR: Retinoid X Receptor

Abstract| Introduction| Materials and Methods| Results| Discussion| Acknowledgment| References|