Dose‐dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by Topiramate

@article{Nallani2003DosedependentIO,
  title={Dose‐dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by Topiramate},
  author={Srikanth C. Nallani and Tracy A. Glauser and Niresh Hariparsad and Kenneth D. R. Setchell and Donna J. Buckley and Arthur R. Buckley and Pankaj B. Desai},
  journal={Epilepsia},
  year={2003},
  volume={44}
}
Summary:  Purpose: In clinical studies, topiramate (TPM) was shown to cause a dose‐dependent increase in the clearance of ethinyl estradiol. We hypothesized that this interaction results from induction of hepatic cytochrome P450 (CYP) 3A4 by TPM. Accordingly, we investigated whether TPM induces CYP3A4 in primary human hepatocytes and activates the human pregnane X receptor (hPXR), a nuclear receptor that serves as a regulator of CYP3A4 transcription. 

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References

SHOWING 1-10 OF 32 REFERENCES

Induction of cytochrome P450 3A4 in primary human hepatocytes and activation of the human pregnane X receptor by tamoxifen and 4-hydroxytamoxifen.

The results indicate that the mechanism of tamoxifen-mediated alteration in drug clearance pathways in humans may involve CYP3A4 induction by the parent drug and/or its metabolite.

The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.

The identification of a human (h) orphan nuclear receptor, termed the pregnane X receptor (PXR), that binds to a response element in the CYP3A4 promoter and is activated by a range of drugs known to induce CYP 3A4 expression is reported.

The Human Nuclear Xenobiotic Receptor PXR: Structural Determinants of Directed Promiscuity

The hydrophobic ligand-binding cavity of hPXR contains a small number of polar residues, permitting SR12813 to bind in three distinct orientations, and the position and nature of these polar residues were found to be critical for establishing the precise pharmacologic activation profile of PXR.

Hepatic but not intestinal CYP3A4 displays dose‐dependent induction by efavirenz in humans

The capacity of the non‐nucleoside reverse transcriptase inhibitor efavirenz to induce either liver CYP3A4 or intestinal CYP3A4, or both, as well as intestinal P‐glycoprotein, was evaluated in

CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes.

  • G. LuoM. Cunningham L. Gan
  • Biology, Medicine
    Drug metabolism and disposition: the biological fate of chemicals
  • 2002
It is concluded that the PXR reporter gene assay is a reliable and complementary method to assess the CYP3A4 induction potential of drugs and other xenobiotics.

Orphan Nuclear Receptors Constitutive Androstane Receptor and Pregnane X Receptor Share Xenobiotic and Steroid Ligands*

It is demonstrated that several of the compounds that regulate mouse and human CAR, including natural steroids, bind directly to the receptors and suggest that CAR, like PXR, is a steroid receptor that is capable of recognizing structurally diverse compounds.

The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution.

PXR is established as a promiscuous xenobiotic receptor that has diverged during evolution through the use of a novel scintillation proximity binding assay, which demonstrates that many of the compounds that induce CYP3A expression bind directly to human PXR.

Increased activity of CYP3A enzyme in primary cultures of rat hepatocytes treated with docetaxel: comparative evaluation with paclitaxel

The possibility that docetaxel at clinically relevant concentrations increases CYP3A activity is raised, as this study investigated the influence of docetAXel on the level and the activity of cytochrome P450 3A in primary cultures of rat hepatocytes.

The Xenobiotic Compound 1,4-Bis[2-(3,5-Dichloropyridyloxy)]Benzene Is an Agonist Ligand for the Nuclear Receptor CAR

It is shown that the nuclear receptor CAR can recognize response elements present in the promoters of xenobiotic-responsive CYP genes, as well as other novel sites, to demonstrate that CAR is a novel xenobiotics receptor that may contribute to the metabolic response to such compounds.

The use of human hepatocyte cultures to study the induction of cytochrome P-450.

The results demonstrate the use of human hepatocyte cultures to investigate the induction of cytochrome P-450 by xenobiotics in intact cells and stress the importance of large dose-response studies as well as the need to assess toxicity in these investigations.