A Link between Cholesterol Levels and Phenobarbital Induction of Cytochromes P450

Ourlin, Jean‐Claude; Handschin, Christoph; Kaufmann, Michel; Meyer, Urs

doi:10.1006/bbrc.2002.6464

Cited by 22 publications

(16 citation statements)

References 28 publications

(36 reference statements)

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“…Notably, by contrast to the other "phenobarbital-like" agents that invariably induce both CYP2B and CYP3A gene products, squalene synthase inhibitor treatments were relatively specific inducers of CYP2B in the rat hepatocyte cultures and in rat liver in vivo; CYP4A, not CYP3A, was the only other P450 that was induced, and this only slightly . Using a chicken hepatoma system, Ourlin et al (2002) recently reported findings that were generally consistent with ours. Thus, squalestatin 1 treatment of LMH cells induced CYP2H1, which was reversed by 25-hydroxycholesterol cotreatment.…”

supporting

confidence: 86%

“…One aspect of our previous work , verified by Ourlin et al (2002), that requires explanation is the observation that squalestatin 1-mediated CYP2B induction was reversed by 25-hydroxysterol cotreatment. Indeed, this classic response was a major finding that led us to hypothesize that the effects of squalestatin 1 on CYP2B expression were secondary to sterol synthesis inhibition and SREBP activation.…”

Section: Discussionmentioning

confidence: 90%

“…In their study, Ourlin et al (2002) hypothesized that endogenous sterols may negatively regulate P450 expression by enabling LXR to outcompete CXR for interaction with the DR4 motifs within the PBRU. In support of their hypothesis, these investigators have recently provided evidence that LXR can bind to the CYP2H1 and CYP2B6 PBRU in vitro, at the same as DR4 sites bound by CXR, CAR, or PXR, and can antagonize the actions of these "xenosensor" receptors.…”

Section: Discussionmentioning

confidence: 99%

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Squalestatin 1-Inducible Expression of Rat CYP2B: Evidence That an Endogenous Isoprenoid Is an Activator of the Constitutive Androstane Receptor

Kocarek

Mercer-Haines

2002

Mol Pharmacol

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Because our previous studies indicated that squalestatin 1 treatment induces CYP2B expression in primary cultures of rat hepatocytes as a direct consequence of squalene synthase inhibition, we investigated possible underlying mechanisms. Cotransfection of cultured Sprague-Dawley male rat hepatocytes with each of the three sterol regulatory element binding protein (SREBP) transcription factors failed to induce luciferase expression from a squalestatin 1-responsive CYP2B1 reporter plasmid. Squalestatin 1 treatment of primary hepatocyte cultures from male Wistar-Kyoto rats produced a greater induction of CYP2B mRNA than occurred in cultures from female rats, consistent with the previously demonstrated response dimorphism that has been attributed to differences in constitutive androstane receptor (CAR) levels. Cotransfection of female Wistar-Kyoto rat hepatocyte cultures with plasmid expressing either mouse or rat CAR restored squalestatin 1-inducible CYP2B1-reporter expression. Cotransfection of Sprague-Dawley rat hepatocyte cultures with plasmid expressing rat CAR lacking the C-terminal AF-2 subdomain inhibited squalestatin 1-inducible CYP2B1-reporter expression. Squalestatin 1-mediated CYP2B mRNA induction in rat hepatocyte cultures was completely abolished by pretreatment with the 3-hydroxymethyl-3-glutaryl CoA reductase inhibitor pravastatin and was rescued by mevalonate supplementation, whereas phenobarbitalmediated induction was unaffected by these treatments. Finally, direct addition of trans,trans-farnesol to the culture medium caused the rapid induction of CYP2B mRNA. These results indicate that squalestatin 1 treatment induces CYP2B expression, not by inhibiting sterol synthesis and activating SREBPs, but by evoking the accumulation of an endogenous isoprenoid and activating CAR.

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supporting

confidence: 86%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Squalestatin 1-Inducible Expression of Rat CYP2B: Evidence That an Endogenous Isoprenoid Is an Activator of the Constitutive Androstane Receptor

Kocarek

Mercer-Haines

2002

Mol Pharmacol

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“…Moreover, transcriptional induction of CYP3A genes by bile acids often exceeds that of CYP2B and CYP2C genes (refs. [92,93] and Carmela Gnerre and U. A. M., unpublished observation).…”

Section: Nuclear Receptor Regulation Of Cholesterol Biosynthesis and mentioning

confidence: 70%

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Handschin¹,

Meyer²

2005

Archives of Biochemistry and Biophysics

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156

105

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Cloning and characterization of the orphan nuclear receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) led to major breakthroughs in studying drug-mediated transcriptional induction of drugmetabolizing cytochromes P450 (CYP). More recently, additional roles for CAR and PXR have been discovered. As examples, these xenosensors are involved in the homeostasis of cholesterol, bile acids, bilirubin and other endogenous hydrophobic molecules in the liver: CAR and PXR thus form an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the cholesterol-sensing liver X receptor (LXR, NR1H2/3) and the bileacid-activated farnesoid X receptor (FXR, NR1H4). In this review, functional interactions between these nuclear receptors as well as the consequences on physiology and pathophysiology of the liver are discussed.Key Words: nuclear receptors; drug-induction; lipids; bile acids; cholesterol; CAR; PXR; LXR; FXR; cytochrome P450 -4 -Metabolism of drugs and other xenobiotics in the liver is our body's primary defense against accumulation of potentially toxic, lipophilic compounds. The superfamily of cytochromes P450 (CYPs) are the best-studied class of enzymes in this task [1]. Transcriptional and post-transcriptional regulation of CYPs after exposure to certain drugs or other xenobiotics has been described several decades ago. Classically, the barbiturate phenobarbital induces its own metabolism and excretion by elevating CYP levels [2]. However, the molecular mechanisms underlying this observation remained a conundrum until the discovery and subsequent characterization of the constitutive androstane receptor (CAR, official nomenclature NR1I3) and the pregnane X receptor (PXR, NR1I2, alternatively called PAR or SXR), two members of the superfamily of nuclear receptors [3][4][5][6][7]. Mice with genetic ablations of CAR and PXR have significantly reduced inducibility of CYPs by a variety of drugs [8,9]. Whereas these two receptors share some common ligands and also have an overlapping target gene pattern [10][11][12][13], the mode of activation for CAR and PXR is quite different [14]. PXR is located in the nucleus, it has a low basal activity and is highly activated upon ligand binding [14,15]. In contrast, in the non-induced state, CAR resides in the cytoplasm. After treatment with activators such as phenobarbital, CAR shuttles to the nucleus to activate its target genes. Moreover, CAR localization and activity is regulated by various protein phosphorylation events [16][17][18]. For a more detailed discussion of CAR and PXR functions in drug-mediated induction of CYPs, see some recent reviews (e.g. refs. [19-23] and references therein).-5 - The nuclear receptor NR1I group includes xenosensors and lipid-sensing membersCompounds that induce transcription of CYPs and that activate CAR and PXR are structurally very diverse [21]. However, most of them are small in size and are highly lipophilic [24]. Whereas the CAR ligand-binding domain stru...

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“…Although LXR and the xenosenors may directly compete for binding to DR-4 sites within PBRUs, it is not clear how LXR inhibits these enhancers, whereas other LXR-responsive DR-4 sites are activated upon LXR binding. In addition, other mechanisms by which so far unknown precursors in the cholesterol biosynthesis pathway activate drug-metabolizing P450s have been proposed; these mechanisms could explain the P450 induction observed after treat-664 ment of rat hepatocytes and chicken hepatoma cells with statins which inhibit cholesterol biosynthesis by an effect on 3-hydroxy-3-methylglutaryl-CoA reductase (Kocarek et al, 1998;Ourlin et al, 2002).…”

Section: A Receptor Cross Talk In Hepatic Drug Inductionmentioning

confidence: 99%

Induction of Drug Metabolism: The Role of Nuclear Receptors

2003

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A Link between Cholesterol Levels and Phenobarbital Induction of Cytochromes P450

Cited by 22 publications

References 28 publications

Squalestatin 1-Inducible Expression of Rat CYP2B: Evidence That an Endogenous Isoprenoid Is an Activator of the Constitutive Androstane Receptor

Squalestatin 1-Inducible Expression of Rat CYP2B: Evidence That an Endogenous Isoprenoid Is an Activator of the Constitutive Androstane Receptor

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Induction of Drug Metabolism: The Role of Nuclear Receptors

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