Roles of the Nuclear Receptors PXR1 and PXR2 in the Regulation of Cytochrome P450 3A11 Expression in Mouse Organs and Primary-Cultured Hepatocytes
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2018, Vol 5, Issue 3
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.Nuclear receptors are ligand-dependent transcription factors that regulate the expression of target genes in response to various stimuli, including physiological factors and environmental factors Evans [1]. The results of genome sequencing have identified 48 nuclear receptors in humans and 49 nuclear receptors in mice Zhang [2]. The identified nuclear receptors include steroid hormone receptors that bind to biological substances such as glucocorticoid and estrogen, and nuclear receptors for which the ligands and physiological functions are unknown Glass [3]. Most of these nuclear receptors interact with lipid-soluble low molecular weight compounds and to contribute to drug metabolism, metabolic disorders such as diabetes and dyslipidemia, cancer cell proliferation, sex differentiation, and regeneration; therefore, nuclear receptors have gained attention as drug targets [4-12,14]. The expression of drug-metabolizing enzymes is regulated by nuclear receptors Sueyoshi & Negishi [13]. Cytochrome P450 (CYP3A), an important drug metabolizing enzyme, is involved in the metabolism of more than 50% of currently available pharmaceutical preparations.Changes in the expression level of CYP3A can alter the effects of many pharmaceutical preparations, affecting drug therapy. The expression level of CYP3A is regulated by nuclear receptors, including pregnane X receptor (PXR) [14-18], Constitutive Androstane Receptor (CAR) [19-21], and Vitamin D receptor (VDR) [22,23]. PXR is known to be highly expressed in the liver [24,25] and small intestine Cheng & Klaassen [26]. This nuclear receptor is typically localized in the cytoplasm in the absence of ligands; however, once activated by ligand binding, it is transferred to the nucleus Glass [3], where it heterodimerizes with retinoid X receptor α (RXR) and activates the transcription of target genes [27,28], by binding to the PXR response elements [16,29,30]. The other main target genes of PXR in addition to CYP3A include uridine diphosphate-glucuronosyltransferase, which has also been implicated in drug metabolism Buckley & Klaassen [31].
Authors and Affiliations
Wataru Ochiai, Ryosuke Miki, Mari Fukuda, Yuya Nakajo, Ryuki Iimura, Jo Hatogai, Shohei Harada, Satoshi Kitaoka, Kiyoshi Sugiyama
Keywords
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- EP ID EP588431
- DOI 10.26717/BJSTR.2018.05.001206
- Views 176
- Downloads 0
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