Omeprazole and Lansoprazole Enantiomers Induce CYP3A4 in Human Hepatocytes and Cell Lines via Glucocorticoid Receptor and Pregnane X Receptor Axis

Novotná, Aneta; Dvořák, Zdeněk

doi:10.1371/journal.pone.0105580

Cited by 30 publications

(25 citation statements)

References 17 publications

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“…SP treatment significantly attenuated this induction. About 2-fold CYP3A4 mRNA induction by RIF was observed in HepG2 cells by other groups at longer time points (Novotna and Dvorak, 2014). These results were in agreement with our CYP3A4 luciferase activity data in transfected HepG2 cells.…”

Section: Resultssupporting

confidence: 92%

Role of c-Jun-N-Terminal Kinase in Pregnane X Receptor-Mediated Induction of Human Cytochrome P4503A4 In Vitro

Taneja¹,

Cai²,

Maturu³

et al. 2018

Drug Metab Dispos

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Cytochrome P450 CYP3A4 is the most abundant drug-metabolizing enzyme and is responsible for the metabolism of ∼50% of clinically available drugs. Induction of CYP3A4 impacts the disposition of its substrates and leads to harmful clinical consequences, such as failure of therapy. To prevent such undesirable consequences, the molecular mechanisms of regulation of CYP3A4 need to be fully understood. induction is regulated primarily by the xenobiotic nuclear receptor pregnane-X receptor (PXR). After ligand binding, PXR is translocated to the nucleus, where it binds to the promoter and induces its gene expression. PXR function is modulated by phosphorylation(s) by multiple kinases. In this study, we determined the role of the c-Jun N-terminal kinase (JNK) in PXR-mediated induction of CYP3A4 enzyme in vitro. Human liver carcinoma cells (HepG2) were transfected with CYP3A4 luciferase and PXR plasmids, followed by treatment with JNK inhibitor (SP600125; SP) and PXR activators rifampicin (RIF) or hyperforin. Our results indicate that SP treatment significantly attenuated PXR-mediated induction of reporter activity, as well as gene expression and enzyme activity. JNK knockdown by siRNA (targeting both JNK 1 and 2) also attenuated CYP3A4 induction by RIF. Interestingly, SP treatment attenuated JNK activation by RIF. Furthermore, treatment with RIF increased PXR nuclear levels and binding to the promoter; SP attenuated these effects. This study shows that JNK is a novel mechanistic regulator of CYP3A4 induction by PXR.

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Section: Resultssupporting

confidence: 92%

Role of c-Jun-N-Terminal Kinase in Pregnane X Receptor-Mediated Induction of Human Cytochrome P4503A4 In Vitro

Taneja¹,

Cai²,

Maturu³

et al. 2018

Drug Metab Dispos

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“…Thus, it is tempting to speculate that the increase in the Bacteroidales S24.7 group could be triggered by the BA activation of these competition mechanisms to increase the fitness of these microorganisms in the highly populated and competitive gut environment. A similar molecular mechanism involving changes in the BA profile may contribute to the gut dysbiosis recently reported among proton pump inhibitor users [ 55 ], since those therapeutics also induce PXR-mediated transcriptional activity [ 56 ].…”

Section: Discussionmentioning

confidence: 90%

Statin therapy causes gut dysbiosis in mice through a PXR-dependent mechanism

et al. 2017

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BackgroundStatins are a class of therapeutics used to regulate serum cholesterol and reduce the risk of heart disease. Although statins are highly effective in removing cholesterol from the blood, their consumption has been linked to potential adverse effects in some individuals. The most common events associated with statin intolerance are myopathy and increased risk of developing type 2 diabetes mellitus. However, the pathological mechanism through which statins cause these adverse effects is not well understood.ResultsUsing a murine model, we describe for the first time profound changes in the microbial composition of the gut following statin treatment. This remodelling affected the diversity and metabolic profile of the gut microbiota and was associated with reduced production of butyrate. Statins altered both the size and composition of the bile acid pool in the intestine, tentatively explaining the observed gut dysbiosis. As also observed in patients, statin-treated mice trended towards increased fasting blood glucose levels and weight gain compared to controls. Statin treatment affected the hepatic expression of genes involved in lipid and glucose metabolism. Using gene knockout mice, we demonstrated that the observed effects were mediated through pregnane X receptor (PXR).ConclusionThis study demonstrates that statin therapy drives a profound remodelling of the gut microbiota, hepatic gene deregulation and metabolic alterations in mice through a PXR-dependent mechanism. Since the demonstrated importance of the intestinal microbial community in host health, this work provides new perspectives to help prevent the statin-associated unintended metabolic effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s40168-017-0312-4) contains supplementary material, which is available to authorized users.

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“…Human CYP3A4 plays an important role in the metabolism of 60% of clinical drugs and is responsible for many drug-drug interactions owing to inducibility by numerous inducers (Liu et al, 2007;Raucy, 2003;Novotna and Dvorak, 2014). Drugdrug interactions caused by the induction of CYP3A4 have posed many challenges to drug development and clinical safety (Niemi et al, 2003;Cheng et al, 2009;Baciewicz et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Alterations of Histone Modifications Contribute to Pregnane X Receptor-Mediated Induction of CYP3A4 by Rifampicin

et al. 2017

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CYP3A4 is one of the major drug-metabolizing enzymes in human and is responsible for the metabolism of 60% of clinically used drugs. Many drugs are able to induce the expression of CYP3A4, which usually causes drug-drug interactions and adverse drug reactions. This study aims to explore the role of histone modifications in rifampicin-induced expression of CYP3A4 in LS174T cells. We found that the induction of CYP3A4 mRNA (4- to 15-fold) by rifampicin in LS174T cells was associated with increased levels of histone H3 lysine 4 trimethylation (H3K4me3, above 1.8-fold) and H3 acetylation (above 2-fold) and a decreased level of histone H3 lysine 27 trimethylation (H3K27me3, about 50%) in the promoter. Rifampicin enhanced recruitment to the promoter of nuclear receptor coactivator 6 (NCOA6, above 3-fold) and histone acetyltransferase p300 (p300, above 1.6-fold). Silencing NCOA6 or p300 by short-hairpin RNAs resulted in inhibition of the CYP3A4 induction as well as altered levels of H3K4me3, H3K27me3, or H3 acetylation in the promoter. Knockdown of pregnane X receptor (PXR) expression not only suppressed the recruitment of NCOA6 and p300 but also abolished the changes caused by rifampicin in H3K4me3, H3K27me3, and H3 acetylation levels in the promoter. Moreover, rifampicin treatment enhanced the nuclear accumulation and interactions between PXR and NCOA6/p300. In conclusion, we show that the alterations of histone modifications contribute to the PXR-mediated induction of CYP3A4 by rifampicin.

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Omeprazole and Lansoprazole Enantiomers Induce CYP3A4 in Human Hepatocytes and Cell Lines via Glucocorticoid Receptor and Pregnane X Receptor Axis

Cited by 30 publications

References 17 publications

Role of c-Jun-N-Terminal Kinase in Pregnane X Receptor-Mediated Induction of Human Cytochrome P4503A4 In Vitro

Role of c-Jun-N-Terminal Kinase in Pregnane X Receptor-Mediated Induction of Human Cytochrome P4503A4 In Vitro

Statin therapy causes gut dysbiosis in mice through a PXR-dependent mechanism

Alterations of Histone Modifications Contribute to Pregnane X Receptor-Mediated Induction of CYP3A4 by Rifampicin

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