AhR and PPAR<i>a</i>: antagonistic effects on CYP2B and CYP3A, and additive inhibitory effects on CYP2C11

Shaban, Zein; Soliman, Mohamed Mohamed; El-Shazly, Samir Ahmed; Elbohi, Khlood M.; Abdelazeez, A.; Kehelo, K.; Kim, H.-S.; Muzandu, Kaampwe; Ishizuka, Mayumi; Kazusaka, Akio; Fujita, Satoshi

doi:10.1080/00498250400021804

Cited by 33 publications

(23 citation statements)

References 56 publications

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“…CAR was induced by EMD, correlating with strong increases in Cyp2B mRNA expression in rats in vivo and in vitro. It has been previously reported that PPAR␣ agonists have the potential to induce Cyp2B and lead to the suppression of Cyp2C11 in rats both on protein and mRNA levels (Shaban et al, 2005), further confirming that EMD is a potent PPAR␣ agonist in rats. In monkeys, CYP2B6 was repressed after 4 weeks and remained unchanged after 17 weeks.…”

Section: Discussionsupporting

confidence: 56%

Species Differences in the Response of Liver Drug-Metabolizing Enzymes to (S)-4-O-Tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric Acid (EMD 392949) in Vivo and in Vitro

Richert¹,

Tuschl²,

Viollon-Abadie³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Induction of drug-metabolizing enzymes (DMEs) is highly speciesspecific and can lead to drug-drug interaction and toxicities. In this series of studies we tested the species specificity of the antidiabetic drug development candidate and mixed peroxisome proliferator-activated receptor (PPAR) ␣/␥ agonist (S)-4-O-tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric acid (EMD 392949, EMD) with regard to the induction of gene expression and activities of DMEs, their regulators, and typical PPAR target genes. EMD clearly induced PPAR␣ target genes in rats in vivo and in rat hepatocytes but lacked significant induction of DMEs, except for cytochrome P450 (P450) 4A. CYP2C and CYP3A were consistently induced in livers of EMD-treated monkeys. Interestingly, classic rodent peroxisomal proliferation markers were induced in monkeys after 17 weeks but not after a 4-week treatment, a fact also observed in human hepatocytes after 72 h but not 24 h of EMD treatment. In human hepatocyte cultures, EMD showed similar gene expression profiles and induction of P450 activities as in monkeys, indicating that the monkey is predictive for human P450 induction by EMD. In addition, EMD induced a similar gene expression pattern as the PPAR␣ agonist fenofibrate in primary rat and human hepatocyte cultures. In conclusion, these data showed an excellent correlation of in vivo data on DME gene expression and activity levels with results generated in hepatocyte monolayer cultures, enabling a solid estimation of human P450 induction. This study also clearly highlighted major differences between primates and rodents in the regulation of major inducible P450s, with evidence of CYP3A and CYP2C inducibility by PPAR␣ agonists in monkeys and humans.

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Section: Discussionsupporting

confidence: 56%

Species Differences in the Response of Liver Drug-Metabolizing Enzymes to (S)-4-O-Tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric Acid (EMD 392949) in Vivo and in Vitro

Richert¹,

Tuschl²,

Viollon-Abadie³

et al. 2008

Drug Metab Dispos

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“…Mechanisms of AHR-mediated induction of P450s are partly understood as they have been studied extensively; however, our understanding of P450 suppression is less clear (Riddick et al, 2004). Data from our laboratory (Jones and Riddick, 1996), in agreement with earlier studies (reviewed in Riddick et al, 2003) as well as recent studies (Caron et al, 2005;Shaban et al, 2005), show that exposure of male rats to aromatic hydrocarbons results in the suppression of hepatic CYP2C11 catalytic activity, protein, and mRNA levels via an unknown pretranslational mechanism.…”

supporting

confidence: 81%

Cytochrome P450 2C11 5′-Flanking Region and Promoter Mediate in Vivo Suppression by 3-Methylcholanthrene

Sawaya

Riddick²

2008

Drug Metab Dispos

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ABSTRACT:Aromatic hydrocarbons such as 3-methylcholanthrene (MC) elicit toxic and adaptive responses through the aryl hydrocarbon receptor (AHR). Aromatic hydrocarbons act via an unknown mechanism to suppress the transcription of CYP2C11, a growth hormoneregulated gene encoding the male-specific rat hepatic cytochrome P450 2C11. We hypothesize that suppression of CYP2C11 by aromatic hydrocarbons is mediated by the gene's promoter and 5-flank. Using hydrodynamics-based injections to deliver plasmid DNA to the liver of live rats, we studied the MC responsiveness of luciferase constructs containing 10.1, 5.6, and 2.4 kilobases (kb) of the CYP2C11 5-flank. MC suppressed CYP2C11-luciferase activity of the 10.1-and 5.6-kb constructs to less than 50% of vehicle levels by 24 and 72 h. Luciferase activity of the 2.4-kb CYP2C11 construct was decreased to 63% of vehicle levels 24 h after MC treatment, but no suppression was detected by 72 h. Negative regulatory element(s) responsible for CYP2C11 reporter suppression by MC exist in the proximal 2.4 kb of the 5-flank; however, additional cisacting elements located between ؊5.6 and ؊2.4 kb mediate persistent reporter suppression. As a positive control for AHR activation, MC dramatically induced the luciferase activity of a Cyp1a1-driven luciferase plasmid under AHR control. Modulation of reporter gene activity by MC was accompanied by induction of endogenous CYP1A1 and suppression of endogenous CYP2C11 mRNA/protein. This is the first demonstration of aromatic hydrocarbon-mediated suppression of a CYP2C11-luciferase construct, and this finding suggests that the 5-flanking region and promoter mediate downregulation of this gene in the intact rat.

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“…However, the effects on the expression of CYP arachidonic acid-epoxygenases appear to vary in different tissues. In rats, treatment with fibrates reduced the level of CYP2C11 expression in the liver (21,130,141). This effect could be recapitulated in cultured hepatocytes, but only when the cells were transfected with PPAR␣.…”

Section: Effects Of Ppar␣ Activation On Eet Production and Metabolismmentioning

confidence: 87%

Action of epoxyeicosatrienoic acids on cellular function

Spector

Norris²

2007

American Journal of Physiology-Cell Physiology

414

450

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Epoxyeicosatrienoic acids (EETs), which function primarily as autocrine and paracrine mediators in the cardiovascular and renal systems, are synthesized from arachidonic acid by cytochrome P-450 epoxygenases. They activate smooth muscle large-conductance Ca2+-activated K+ channels, producing hyperpolarization and vasorelaxation. EETs also have anti-inflammatory effects in the vasculature and kidney, stimulate angiogenesis, and have mitogenic effects in the kidney. Many of the functional effects of EETs occur through activation of signal transduction pathways and modulation of gene expression, events probably initiated by binding to a putative cell surface EET receptor. However, EETs are rapidly taken up by cells and are incorporated into and released from phospholipids, suggesting that some functional effects may occur through a direct interaction between the EET and an intracellular effector system. In this regard, EETs and several of their metabolites activate peroxisome proliferator-activated receptor α (PPARα) and PPARγ, suggesting that some functional effects may result from PPAR activation. EETs are metabolized primarily by conversion to dihydroxyeicosatrienoic acids (DHETs), a reaction catalyzed by soluble epoxide hydrolase (sEH). Many potentially beneficial actions of EETs are attenuated upon conversion to DHETs, which do not appear to be essential under routine conditions. Therefore, sEH is considered a potential therapeutic target for enhancing the beneficial functions of EETs.

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AhR and PPARa: antagonistic effects on CYP2B and CYP3A, and additive inhibitory effects on CYP2C11

Cited by 33 publications

References 56 publications

Species Differences in the Response of Liver Drug-Metabolizing Enzymes to (S)-4-O-Tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric Acid (EMD 392949) in Vivo and in Vitro

Species Differences in the Response of Liver Drug-Metabolizing Enzymes to (S)-4-O-Tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric Acid (EMD 392949) in Vivo and in Vitro

Cytochrome P450 2C11 5′-Flanking Region and Promoter Mediate in Vivo Suppression by 3-Methylcholanthrene

Action of epoxyeicosatrienoic acids on cellular function

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