Phenobarbital Confers its Diverse Effects by Activating the Orphan Nuclear Receptor Car

Kodama, Susumu; Negishi, Masahiko

doi:10.1080/03602530600569851

Cited by 69 publications

(46 citation statements)

References 62 publications

(43 reference statements)

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“…For example, although peroxisome proliferators have carcinogenic consequences in the livers of rodents, epidemiological studies have revealed that similar effects are unlikely to occur in humans (25). Additionally, PB has been used for decades as the prototypical nongenotoxic tumor-promoting agent in numerous rodent studies of hepatocarcinogenesis; however, epidemiological studies indicate that PB does not cause liver tumors in humans (26). Although the primary event governing activation of nuclear receptors is ligand binding, increasing amounts of evidence suggest that cell signaling pathways and modulation of nuclear receptor-cofactor-phosphorylation status also determines overall responsiveness to environmental stimuli (27,28).…”

Section: Discussionmentioning

confidence: 99%

Cyclic AMP-dependent Protein Kinase Signaling Modulates Pregnane x Receptor Activity in a Species-specific Manner

Lichti-Kaiser

Staudinger

2009

Journal of Biological Chemistry

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Pregnane x receptor is a ligand-activated transcription factor that regulates drug-inducible expression of several key cytochrome P450 enzymes and drug transporter proteins in liver and intestine in a species-specific manner. Activation of this receptor modulates several key biochemical pathways, including gluconeogenesis, ␤-oxidation of fatty acids, fatty acid uptake, cholesterol homeostasis, and lipogenesis. It is of current interest to determine whether the interaction between pregnane x receptor and these key biochemical pathways is evolutionarily conserved. We show here that activation of the cyclic AMP-dependent protein kinase signaling pathway synergizes with pregnane x receptor-mediated gene activation in mouse hepatocytes. Conversely, cyclic AMP-dependent protein kinase signaling has a repressive effect upon pregnane x receptor-mediated gene activation in rat and human hepatocytes. We show that the human pregnane x receptor protein can serve as an effective substrate for catalytically active cyclic AMP-dependent protein kinase in vitro. Metabolic labeling of the protein in vivo indicates that human pregnane x receptor exists as a phosphoprotein and that activation of cyclic AMP-dependent protein kinase signaling modulates the phosphorylation status of pregnane x receptor. Activation of cyclic AMP-dependent protein kinase signaling also modulates the interactions of pregnane x receptor with protein cofactors. Our results define the species-specific impact of cyclic AMP-dependent protein kinase signaling on pregnane x receptor and provide a molecular explanation of cyclic AMP-dependent protein kinase-mediated repression of human pregnane x receptor activity. Taken together, our results identify a novel mode of regulation of pregnane x receptor activity and highlight prominent functional differences in the process across species.

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Section: Discussionmentioning

confidence: 99%

Cyclic AMP-dependent Protein Kinase Signaling Modulates Pregnane x Receptor Activity in a Species-specific Manner

Lichti-Kaiser

Staudinger

2009

Journal of Biological Chemistry

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“…Interestingly, CAR activation may also occur without direct binding of the ligand to CAR, and this is exemplified by the activation of CAR by phenobarbital and various other compounds (12). The reader is referred to recent reviews on the mechanistic details of direct and indirect activation of CAR (17,80) and the interplay between CAR and other nuclear receptors (19).…”

Section: Constitutive Androstane Receptormentioning

confidence: 99%

Activation of Pregnane X Receptor (PXR) and Constitutive Androstane Receptor (CAR) by Herbal Medicines

Chang

2009

AAPS J

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Abstract. Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are transcription factors that control the expression of a broad array of genes involved not only in transcellular transport and biotransformation of many drugs, other xenochemicals, and endogenous substances, such as bile acid, bilirubin, and certain vitamins, but also in various physiological/pathophysiological processes such as lipid metabolism, glucose homeostasis, and inflammation. Ligands of PXR and CAR are chemicals of diverse structures, including naturally occurring compounds present in herbal medicines. The overall aim of this article is to provide an overview of our current understanding of the role of herbal medicines as modulators of PXR and CAR.

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“…For example, the activation of nuclear receptor CAR by chemicals such as phenobarbital, an anticonvulsant drug, induces various enzymes and transporters, thereby increasing the hepatic activities of drug metabolism and transport (Kodama and Negishi, 2006). CAR target genes include phase I enzymes (e.g., Cyp2b, Cyp2c, and Cyp3a), phase II enzymes (e.g., Sults, Ugts, and Gsts) (Ueda et al, 2002), and transporters such as Mrp2 and Mrp4 (Kast et al, 2002;Assem et al, 2004).…”

Section: Downloaded Frommentioning

confidence: 99%

Energy Restriction Does Not Compensate for the Reduced Expression of Hepatic Drug-Processing Genes in Mice with Aging

Zhang¹,

Saupe²,

Klaassen³

2010

Drug Metab Dispos

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ABSTRACT:Liver is the major organ that eliminates xenobiotics from the body, a process that is accomplished by a series of drug-processing genes (DPGs). These genes encode transporters on both basolateral and apical membranes of hepatocytes, as well as phase I and II enzymes. The current study compares the expression of hepatic DPGs in adult and aged mouse livers and explores the potential effects of energy restriction (ER) on these genes during aging. Of 79 quantified hepatic DPGs, 52 were expressed lower in 24-monthold aged mice than in 12-month-old adult mice. Furthermore, the mRNA expression of multiple xenobiotic-activated transcription factors also decreased with age. Six-month ER exerted less of an effect on the hepatic DPGs than did aging. ER increased the mRNAs of two and decreased the mRNAs of nine DPGs in adult mice. In aged mice, ER increased the mRNAs of 10 and decreased the mRNAs of 5 DPGs. The only mRNA that was increased by both ER and aging was Gstm3. ER increased the mRNAs of Cyp2b10, Ugt1a9, Gsta1, and Oatp1a4 only in adult mice and decreased the mRNAs of Aldh6a1, Pon3, Ugt1a1, Sult1a1, and Atp8b1 only in aged mice. In summary, the reduced mRNA expression of hepatic DPGs in aged mice indicates decreased drug-processing capability, whereas ER did not compensate for the global reduction of hepatic DPG expression in aged mice. The hepatic transcription factors are likely to mediate the changes in hepatic DPG expression during aging and ER.The geriatric population is rapidly increasing in the world. The proportion of persons aged 60 or older is projected to reach 22% of the global population in 2050, with 33% in more developed regions and 20% in less developed regions (United Nations Population Ageing and Development 2009, http://www.un.org/esa/population/ publications/ageing/ageing2009chart.pdf). Health care for this population presents a major medical and economic problem. The elderly population is more susceptible to various diseases, and they often take several drugs at the same time. Liver, the major organ for drug elimination from the body, exhibits decreased volume, diminished hepatobiliary functions, declined phase I drug metabolism capability, and increased or decreased expression of a variety of proteins in the elderly population (Schmucker, 2005).Liver metabolizes endogenous and exogenous compounds (nutrients and drugs), as well as maintains energy balance in the body. Numerous liver functions are accomplished by proteins encoded by a series of drug-processing genes (DPGs), which include basolateral uptake transporters, phase I and II enzymes, and apical and basolateral efflux transporters.Hepatocytes have transporters on both their basolateral and apical sides to remove xenobiotics from intestine-derived portal blood and to excrete them or their metabolites into bile or blood. Uptake solute carriers include organic anion-transporting polypeptides (Oatps), sodium/taurocholate-cotransporting polypeptide (Ntcp), organic cation transporters (Octs), organic anion transporters (Oats), and so...

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Phenobarbital Confers its Diverse Effects by Activating the Orphan Nuclear Receptor Car

Cited by 69 publications

References 62 publications

Cyclic AMP-dependent Protein Kinase Signaling Modulates Pregnane x Receptor Activity in a Species-specific Manner

Cyclic AMP-dependent Protein Kinase Signaling Modulates Pregnane x Receptor Activity in a Species-specific Manner

Activation of Pregnane X Receptor (PXR) and Constitutive Androstane Receptor (CAR) by Herbal Medicines

Energy Restriction Does Not Compensate for the Reduced Expression of Hepatic Drug-Processing Genes in Mice with Aging

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