Pregnane X receptor: molecular basis for species differences in CYP3A induction by xenobiotics

doi:10.1016/S0009-2797(01)00163-6

Chemico-Biological Interactions

Volume 134, Issue 3, 16 May 2001, Pages 283-289

https://doi.org/10.1016/S0009-2797(01)00163-6 Get rights and content

Abstract

Determining the molecular basis for the observed species differences in the xenobiotic-mediated induction of cytochrome 3A (CYP3A) gene expression has become one of the biggest dilemmas of the modern era in toxicology. Recently, a novel orphan nuclear receptor, termed pregnane X receptor (PXR), has been implicated to play a key role in the regulation of CYP3A genes by xenobiotics. PXR is capable of binding to and activating transcription from specific response elements found in the CYP3A gene promoter from multiple species. Notably, compounds that are known to induce CYP3A selectively in human, mouse, rat, or rabbit also activate the corresponding PXR. Pregnenolone 16α-carbonitrile, a known CYP3A inducer in rodents, is a very efficacious activator of mouse and rat PXR, whereas rifampicin, a known inducer of CYP3A in humans and rabbits, is a very efficacious activator of human and rabbit PXR. Likewise, selective activators of PXR also induce CYP3A gene expression in the corresponding species. Orthologous receptors from human, mouse, rat, and rabbit have been cloned and characterized and share approx. 95% identity in their DNA binding domains. By contrast, they share only 75–80% identity in their amino acid sequences in the ligand-binding domain. Together, these data suggest that PXR is a critical regulator of CYP3A gene expression and activation of PXR is predictive of CYP3A induction. Furthermore, sequence differences in the ligand-binding domain, and not the DNA binding domain, appear to serve as the molecular basis for the species differences in CYP3A induction observed in vivo.

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Acknowledgements

The author would like to acknowledge the contributions of Jennifer Shenk, Linda Moore, Stacey Jones, and Steven Kliewer from the Department of Molecular Endocrinology, GlaxoWellcome, Inc.; Geraldine Hamilton, Summer Jolley, James Coon, and Darryl Gilbert from the Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina at Chapel Hill; and Bingfang Yan from the Department of Biomedical Sciences, University of Rhode Island.

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Considering the species-related differences of activation for both PXR and CAR between human and rodent (LeCluyse, 2001), the induction of CYPs by SinB and SolB in the clinic was warranted.
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Pregnane X receptor: molecular basis for species differences in CYP3A induction by xenobiotics

Abstract

Section snippets

Acknowledgements

Toxicol. Appl. Pharmacol.

Cell

Arch. Biochem. Biophys.

The CYP3A family

Regulation of the glucocorticoid-inducible cytochromes P450

Comparative analysis of cytochrome P4503A induction in primary cultures of rat, rabbit, and human hepatocyes

Drug Met. Dispos.

Trans-species gene transfer for analysis of glucocorticoid-inducible transcriptional activation of transiently expressed human CYP3A4 and rabbit CYP3A6 in primary cultures of adult rat and rabbit hepatocytes

Mol. Pharmacol.