Regulation of CYP3A4 Expression in Human Hepatocytes by Pharmaceuticals and Natural Products

Raucy, Judy L.

doi:10.1124/dmd.31.5.533

Cited by 223 publications

(136 citation statements)

References 23 publications

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“…However, this same concentration of PHY does not activate hPXR significantly in either HepG2 or Huh7 cells as assessed by CYP2B6 reporter gene activity. These results are in agreement with a previous report by Raucy et al (29), where only minor activation of PXR was observed with PHY at concentrations up to 1 mM in HepG2 cells (29). These initial results provided the first inclination that hPXR may not be the primary mediator of PHY induction of CYP2B6 gene expression.…”

Section: Phy Activates and Translocates Hcar In Vivo Insupporting

confidence: 83%

Human Constitutive Androstane Receptor Mediates Induction of CYP2B6 Gene Expression by Phenytoin

Wang

Faucette

Moore

et al. 2004

Journal of Biological Chemistry

139

100

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Compared with its rodent orthologs, little is known about the chemical specificity of human constitutive androstane receptor (hCAR) and its regulation of hepatic enzyme expression. Phenytoin (PHY), a widely used antiepileptic drug, is a potent inducer of CYP2B6 in primary human hepatocytes, but does not activate human pregnane X receptor (PXR) significantly in cellbased transfection assays at the same concentrations associated with potent induction of CYP2B6. Based on this observation, we hypothesized that PHY may be a selective activator of hCAR. In primary human hepatocytes, expression of CYP2B6 reporter genes containing phenobarbital-responsive enhancer module (PBREM) or PBREM/xenobiotic-responsive enhancer module (XREM) response elements were activated up to 14-and 28-fold, respectively, by 50 M PHY. By contrast, parallel experiments in HepG2 cell lines co-transfected with an hPXR expression vector did not show increased reporter activity. These results indicated that a PXR-independent pathway, which is retained in primary hepatocytes, is responsible for PHY induction of CYP2B6. Further experiments revealed that PHY effectively translocates hCAR from the cytoplasm into the nucleus in both primary human hepatocytes and CAR ؊/؊ mice. Compared with vehicle controls, PHY administration significantly increased CYP2B6 reporter gene expression, when this reporter construct was delivered together with hCAR expression vector into CAR ؊/؊ mice. However, PHY did not increase reporter gene expression in CAR ؊/؊ mice in the absence of hCAR vector, implying that CAR is essential for mediating PHY induction of CYP2B6 gene expression. Taken together, these observations demonstrate that, in contrast to most of the known CYP2B6 inducers, PHY is a selective activator of CAR in humans.Induction of cytochrome P450 2B (CYP2B) 1 expression by xenobiotics, including clinically used drugs, is mediated by activation of the nuclear receptors constitutive androstane receptor (CAR) and/or pregnane X receptor (PXR) through response elements located in the promoter region of CYP2B genes. In contrast to rodent CYP2B genes, mounting evidence suggests that human PXR (hPXR) may be a key receptor in the regulation of human CYP2B6 gene expression (1-3). hPXR ligands, including rifampicin (RIF), phenobarbital (PB), troglitazone, clotrimazole (CLZ), and SR12813 have been reported to induce CYP2B6 gene expression (1, 4 -7). Recently, fourteen commercially available compounds, including weak, moderate, and strong inducers of CYP2B6 and CYP3A4, were used to compare the potency and magnitude of CYP2B6 and CYP3A4 induction and activation of hPXR in primary cultured hepatocytes and hepatoma cell-based reporter gene assays, respectively. Results from these studies indicate that CYP2B6 induction is highly correlated with the activation of hPXR for most compounds (3). Among the efficacious CYP2B6 inducers evaluated, most activate hPXR but not hCAR, such as RIF and CLZ (CLZ was even reported as a hCAR deactivator by Moore et al. (8)), whereas others can a...

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Section: Phy Activates and Translocates Hcar In Vivo Insupporting

confidence: 83%

Human Constitutive Androstane Receptor Mediates Induction of CYP2B6 Gene Expression by Phenytoin

Wang

Faucette

Moore

et al. 2004

Journal of Biological Chemistry

139

100

View full text Add to dashboard Cite

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“…However, when a reporter gene assay with hPXR was used, quercetin did not show a significant increase in luciferase activity, suggesting that CYP3A4 was induced by mechanisms not involving PXR. Herbs like grapeseed extract, ginseng, garlic, and kava-kava also increased CYP3A4 mRNA levels in hepatocytes, but of these botanicals, only kava-kava produced enhanced luciferase activity [61]. The results of that study clearly showed that some CAMs have the potential to induce CYP3A4, although not always mediated via PXR.…”

Section: In Vitrosupporting

confidence: 52%

“…Raucy [61] used CYP3A4 mRNA analysis in primary cultures of human hepatocytes of 17 individuals to test the inductive properties of several flavonoids, including quercetin, resveratrol, and curcumin. Of these, only quercetin produced accumulation of CYP3A4 mRNA.…”

Section: In Vitromentioning

confidence: 99%

Herb–Drug Interactions in Oncology: Focus on Mechanisms of Induction

2006

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An increasing number of cancer patients are using complementary and alternative medicines (CAM) in combination with their conventional chemotherapeutic treatment. Considering the narrow therapeutic window of oncolytic drugs, this CAM use increases the risk of clinically relevant herb-anticancer drug interactions. Such a relevant interaction is that of St. John's wort with the anticancer drugs irinotecan and imatinib. It is, however, estimated that CAM-anticancer drug interactions are responsible for substantially more unexpected toxicities of chemotherapeutic drugs and possible undertreatment seen in cancer patients.Induction of drug-metabolizing enzymes and ATP-binding cassette drug transporters can be one of the mechanisms behind CAM-anticancer drug interactions. Induction will often lead to therapeutic failure because of lower plasma levels of the anticancer drugs, and will easily go unrecognized in cancer treatment, where therapeutic failure is common.Recently identified nuclear receptors, such as the pregnane X receptor, the constitutive androstane receptor, and the vitamin D-binding receptor, play an important role in the induction of metabolizing enzymes and drug transporters. This knowledge has already been an aid in the identification of some CAM probably capable of causing interactions with anticancer drugs: kavakava, vitamin E, quercetin, ginseng, garlic, β-carotene, and echinacea. Evidently, more research is necessary to prevent therapeutic failure and toxicity in cancer patients and to establish guidelines for CAM use. The Oncologist 2006;11:742-752 Learning ObjectivesAfter completing this course, the reader will be able to:1. Describe the possible pharmacokinetic interactions between complementary alternative medicines and oncolytic drugs and the clinical consequences thereof.2. Define the role of the nuclear receptors PXR, CAR, and VDR in herb-drug interactions.3. Discuss methods to measure induction of drug-metabolizing enzymes and transporters.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit

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“…To further elucidate the involvement of PXR, a reporter gene assay with hPXR was used. Quercetin did not show a significant increase in luciferase activity, suggesting that CYP3A4 was induced by mechanisms not involving PXR (105). Kava-kava also increases CYP3A4 mRNA levels in hepatocytes with enhanced luciferase activity, others like grapeseed extract, ginseng and garlic stimulates only CYP3A4 mRNA without increasing luciferase activity indicating that that the induction CYP3A4 by some herbs may not always be mediated via PXR.…”

Section: Investigating Herb-drug Interactionmentioning

confidence: 90%

Pharmacokinetics and Drug Interactions of Herbal Medicines: A Missing Critical Step in the Phytomedicine/Drug Development Process

Obodozie¹

2012

Readings in Advanced Pharmacokinetics - Theory, Methods and Applications

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Regulation of CYP3A4 Expression in Human Hepatocytes by Pharmaceuticals and Natural Products

Cited by 223 publications

References 23 publications

Human Constitutive Androstane Receptor Mediates Induction of CYP2B6 Gene Expression by Phenytoin

Human Constitutive Androstane Receptor Mediates Induction of CYP2B6 Gene Expression by Phenytoin

Herb–Drug Interactions in Oncology: Focus on Mechanisms of Induction

Pharmacokinetics and Drug Interactions of Herbal Medicines: A Missing Critical Step in the Phytomedicine/Drug Development Process

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