5-Aminoimidazole-4-carboxamide-1-.BETA.-ribofuranoside (AICAR) prevents nuclear translocation of constitutive androstane receptor by AMP-activated protein kinase (AMPK) independent manner

Kanno, Yuichiro; Inoue, Yoshimi; Inouye, Yoshio

doi:10.2131/jts.35.571

Cited by 15 publications

(11 citation statements)

References 18 publications

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“…In a different study, Shindo et al (2007) demonstrated that metformin and AICAR induced CAR nuclear translocation but failed to induce hepatic CYP2B gene in mouse and rat livers. In contrast, another study revealed AICAR but not metformin prevented nuclear translocation of CAR and repressed PBinduced CYP2B expression in rat primary hepatocytes (Kanno et al, 2010).…”

Section: Discussionmentioning

confidence: 82%

Metformin Represses Drug-Induced Expression of CYP2B6 by Modulating the Constitutive Androstane Receptor Signaling

et al. 2013

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Metformin is currently the most widely used drug for the treatment of type 2 diabetes. Mechanistically, metformin interacts with many protein kinases and transcription factors that alter the expression of numerous downstream target genes governing lipid metabolism, cell proliferation, and drug metabolism. The constitutive androstane receptor (CAR, NR1i3), a known xenobiotic sensor, has recently been recognized as a novel signaling molecule, in that its activation could be regulated by protein kinases in addition to the traditional ligand binding. We show that metformin could suppress drug-induced expression of CYP2B6 (a typical target gene of CAR) by modulating the phosphorylation status of CAR. In human hepatocytes, metformin robustly suppressed the expression of CYP2B6 induced by both indirect (phenobarbital) and direct CITCO [6-(4-chlorophenyl)imidazo[2,1-b]1,3thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime] activators of human CAR. Mechanistic investigation revealed that metformin specifically enhanced the phosphorylation of threonine-38 of CAR, which blocks CAR nuclear translocation and activation. Moreover, we showed that phosphorylation of CAR by metformin was primarily an AMP-activated protein kinase-and extracellular signal-regulated kinase 1/2-dependent event. Additional two-hybrid and coimmunoprecipitation assays demonstrated that metformin could also disrupt CITCO-mediated interaction between CAR and the steroid receptor coactivator 1 or the glucocorticoid receptorinteracting protein 1. Our results suggest that metformin is a potent repressor of drug-induced CYP2B6 expression through specific inhibition of human CAR activation. Thus, metformin may affect the metabolism and clearance of drugs that are CYP2B6 substrates.

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Section: Discussionmentioning

confidence: 82%

Metformin Represses Drug-Induced Expression of CYP2B6 by Modulating the Constitutive Androstane Receptor Signaling

et al. 2013

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“…AMPK activation has previously been shown to promote phosphorylation and regulate the localization of constitutive androstane receptor (CAR) in cells293031. Therefore, we performed an in vitro kinase assay to determine if PXR was a direct target of AMPK.…”

Section: Resultsmentioning

confidence: 99%

“…The gluconeogenic transcription factor forkhead box transcription factor O1 (FoxO1) regulates the transactivation of both constitutive androstane receptor (CAR) and PXR target genes28. Also, AMPK regulates CAR, but the exact nature of this regulation remains unclear293031. To further delineate the crosstalk between the drug metabolism and energy metabolism pathways, we examined the glucose-dependent regulation of PXR in this study.…”

mentioning

confidence: 99%

Glucose-dependent regulation of pregnane X receptor is modulated by AMP-activated protein kinase

Oladimeji

Lin

Brewer

et al. 2017

Sci Rep

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Pregnane X receptor (PXR) is a xenobiotic receptor that regulates the detoxification and clearance of drugs and foreign compounds from the liver. There has been mounting evidence of crosstalk between the drug metabolism pathway and the energy metabolism pathway, but little is known about this cross-regulation. To further delineate the energy metabolism and drug metabolism crosstalk in this study, we exposed HepG2 cells to varying glucose concentrations. We observed that PXR activity was induced under high-glucose conditions. This finding is consistent with previous clinical reports of increased drug clearance in patients with untreated diabetes. We demonstrated that AMP-activated protein kinase (AMPK) modulates PXR transcriptional activity and that pharmacologically manipulated AMPK activation exhibits an inverse relation to PXR activity. Activation of AMPK was shown to downregulate PXR activity and, consistent with that, potentiate the response of cells to the drug. Taken together, our results delineate a hitherto unreported axis of regulation that involves the energy status of the cell, PXR regulation, and drug sensitivity.

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“…A segment of the receptor interaction domain (RID) of steroid receptor coactivator 1 (SRC1) (Leo and Chen, 2000) (SRC1/RID, 569-781) was cloned into pcDNA5-GAL4/DBD. The expression plasmids for human CAR (hCAR)/LBD fused with GAL4/DBD were described previously (Kanno et al, 2010). The preparation of the XREM-driven luciferase reporter plasmid (XREM-luc) has been described elsewhere (Kanno et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

“…The expression plasmids for human CAR (hCAR)/LBD fused with GAL4/DBD were described previously (Kanno et al, 2010). The preparation of the XREM-driven luciferase reporter plasmid (XREM-luc) has been described elsewhere (Kanno et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

Nigramide C Is a Natural Agonist of Human Pregnane X Receptor

Kanno¹,

Yatsu²,

Li³

et al. 2014

Drug Metab Dispos

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Pregnane X receptor (PXR) is known as a xenosensor, playing a key role in response to xenochemical stimuli. Activation of PXR enhanced expression of various drug-metabolizing enzymes and transporters such as cytochrome P450 3A4 (CYP3A4). During a screening of a natural compounds library for novel ligands of human xenosensing receptors by the mammalian one-hybrid assay, two cyclohexene-type amide alkaloids were isolated, with nigramide C (NigC) showing the most potent activation of human PXR (hPXR). NigC-mediated hPXR activation was enhanced by overexpression of steroid receptor coactivator 1 (SRC1), peroxisome proliferator-activated receptor g, coactivator 1a, and protein arginine methyltransferase 1. A direct interaction between the ligand-binding domain of hPXR and the receptor interaction domain of SRC1 was observed. NigC induced the expression of endogenous CYP3A4 mRNA and protein in both cultured hepatoma cells and primary hepatocytes. However, in primary hepatocytes, the relative agonist activity of NigC was not as potent as that of rifampicin, probably because of lower metabolic stability of NigC in these cells. In conclusion, NigC was found to be an effective agonist of hPXR. NigC is a useful tool for investigation of hPXR function.

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5-Aminoimidazole-4-carboxamide-1-.BETA.-ribofuranoside (AICAR) prevents nuclear translocation of constitutive androstane receptor by AMP-activated protein kinase (AMPK) independent manner

Cited by 15 publications

References 18 publications

Metformin Represses Drug-Induced Expression of CYP2B6 by Modulating the Constitutive Androstane Receptor Signaling

Metformin Represses Drug-Induced Expression of CYP2B6 by Modulating the Constitutive Androstane Receptor Signaling

Glucose-dependent regulation of pregnane X receptor is modulated by AMP-activated protein kinase

Nigramide C Is a Natural Agonist of Human Pregnane X Receptor

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