Role of Constitutive Androstane Receptor in Toll-Like Receptor-Mediated Regulation of Gene Expression of Hepatic Drug-Metabolizing Enzymes and Transporters

Shah, Pranav; Guo, Tao; Moore, David D.; Ghose, Romi

doi:10.1124/dmd.113.053850

Cited by 32 publications

(21 citation statements)

References 31 publications

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“…Although engagement of other intracellular receptors, including Toll-like receptors, has been implicated in the regulation of CYP3A during infection (Shah et al, 2014), we now provide evidence supporting the notion that extracellular receptors influence hepatic drug metabolism under infectious and noninfectious conditions. These results may translate beyond CYP3A activity because several nuclear receptors that regulate it play notable roles in the regulation of other metabolic enzymes and drug transporters.…”

Section: Discussionsupporting

confidence: 48%

Integrin Receptors Play a Key Role in the Regulation of Hepatic CYP3A

Jonsson-Schmunk

Wonganan

Choi

et al. 2016

Drug Metabolism and Disposition

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Landmark studies describing the effect of microbial infection on the expression and activity of hepatic CYP3A used bacterial lipopolysaccharide as a model antigen. Our efforts to determine whether these findings were translatable to viral infections led us to observations suggesting that engagement of integrin receptors is key in the initiation of processes responsible for changes in hepatic CYP3A4 during infection and inflammation. Studies outlined in this article were designed to evaluate whether engagement of integrins, receptors commonly used by a variety of microbes to enter cellular targets, is vital in the regulation of CYP3A in the presence and absence of virus infection. Mice infected with a recombinant adenovirus (AdlacZ) experienced a 70% reduction in hepatic CYP3A catalytic activity. Infection with a mutant virus with integrin-binding arginine-glycine-aspartic acid (RGD) sequences deleted from the penton base protein of the virus capsid (AdDRGD) did not alter CYP3A activity. CYP3A mRNA and protein levels in AdlacZtreated animals were also suppressed, whereas those of mice given AdDRGD were not significantly different from uninfected control mice. Silencing of the integrin b-subunit reverted adenovirus-mediated CYP3A4 suppression in vitro. Silencing of the a-subunit did not. Suppression of integrin subunits had a profound effect on nuclear receptors pregnane X receptor and constitutive androstane receptor, whereas retinoid X receptor a was largely unaffected. To our knowledge, this is the first time that extracellular receptors, like integrins, have been indicated in the regulation of CYP3A. This finding has several implications owing to the important role of integrins in normal physiologic process and in many disease states.

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Section: Discussionsupporting

confidence: 48%

Integrin Receptors Play a Key Role in the Regulation of Hepatic CYP3A

Jonsson-Schmunk

Wonganan

Choi

et al. 2016

Drug Metabolism and Disposition

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“…This may be because inflammatory stress cannot up-regulate the transcriptional regulators of CD36 including LXR, PXR and PPARγ in liver [6], [37].…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Stress Increases Hepatic CD36 Translational Efficiency via Activation of the mTOR Signalling Pathway

Wang

Zhao

et al. 2014

PLoS ONE

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Inflammatory stress is an independent risk factor for the development of non-alcoholic fatty liver disease (NAFLD). Although CD36 is known to facilitate long-chain fatty acid uptake and contributes to NAFLD progression, the mechanisms that link inflammatory stress to hepatic CD36 expression and steatosis remain unclear. As the mammalian target of rapamycin (mTOR) signalling pathway is involved in CD36 translational activation, this study was undertaken to investigate whether inflammatory stress enhances hepatic CD36 expression via mTOR signalling pathway and the underlying mechanisms. To induce inflammatory stress, we used tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) stimulation of the human hepatoblastoma HepG2 cells in vitro and casein injection in C57BL/6J mice in vivo. The data showed that inflammatory stress increased hepatic CD36 protein levels but had no effect on mRNA expression. A protein degradation assay revealed that CD36 protein stability was not different between HepG2 cells treated with or without TNF-α or IL-6. A polysomal analysis indicated that CD36 translational efficiency was significantly increased by inflammatory stress. Additionally, inflammatory stress enhanced the phosphorylation of mTOR and its downstream translational regulators including p70S6K, 4E-BP1 and eIF4E. Rapamycin, an mTOR-specific inhibitor, reduced the phosphorylation of mTOR signalling pathway and decreased the CD36 translational efficiency and protein level even under inflammatory stress resulting in the alleviation of inflammatory stress-induced hepatic lipid accumulation. This study demonstrates that the activation of the mTOR signalling pathway increases hepatic CD36 translational efficiency, resulting in increased CD36 protein expression under inflammatory stress.

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“…cDNA was synthesized using the high-capacity reverse transcription kit from Applied Biosystems (Foster City, CA). Real-time polymerase chain reaction (PCR) was performed using an ABI PRISM 7300 Sequence Detection System instrument and software (Applied Biosystems) as described previously (Ghose et al, 2004(Ghose et al, , 2007Shah et al, 2014). In short, each 25-ml reaction mixture contained 50-100 ng of cDNA, 300 nM forward primer, 300 nM reverse primer, 200 nM fluorogenic probe, and 15 ml of TaqMan Universal PCR Master Mix.…”

Section: Methodsmentioning

confidence: 99%

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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Role of Constitutive Androstane Receptor in Toll-Like Receptor-Mediated Regulation of Gene Expression of Hepatic Drug-Metabolizing Enzymes and Transporters

Cited by 32 publications

References 31 publications

Integrin Receptors Play a Key Role in the Regulation of Hepatic CYP3A

Integrin Receptors Play a Key Role in the Regulation of Hepatic CYP3A

Inflammatory Stress Increases Hepatic CD36 Translational Efficiency via Activation of the mTOR Signalling Pathway

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

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