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Research ArticleArticle

Rabbit Pregnane X Receptor Is Activated by Rifampicin

Üzen Savas, Michael R. Wester, Keith J. Griffin and Eric F. Johnson
Drug Metabolism and Disposition May 2000, 28 (5) 529-537;
Üzen Savas
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Michael R. Wester
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Keith J. Griffin
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Eric F. Johnson
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Abstract

Reverse transcriptase-polymerase chain reaction was used to amplify a partial cDNA from rabbit lung mRNA that shared 77% protein sequence identity with the mouse pregnane X receptor (PXR). Rapid amplification of cDNA ends from a rabbit kidney λZAP expression library resulted in the isolation of overlapping cDNAs spanning the complete coding sequence. The deduced amino acid sequence of 411 residues exhibited 79% overall amino acid identity with human PXR and 77% identity with mouse PXR. Based on this protein sequence relationship and a similar degree of conservation exhibited by the mouse and human PXR orthologs, the cDNA appears to encode the rabbit PXR ortholog. 5′-rapid amplification of cDNA ends performed on an adaptor-ligated cDNA library from rabbit liver revealed the presence of an alternate mRNA, which differed at the 5′-terminus. RNase protection assays indicated that the alternate mRNA was expressed at >50-fold lower levels in rabbit kidney and liver. Rifampicin treatment of CV-1 cells cotransfected with a rabbit PXR expression plasmid and a luciferase reporter construct containing two copies of the DR3 enhancer from CYP3A23 produced a 6-fold induction of luciferase activity. In contrast, rat PXR was not responsive to this antibiotic under the same conditions. Pregnenolone 16α-carbonitrile was an efficacious activator of rat PXR, but failed to significantly activate rabbit PXR at equivalent concentrations. These results indicate that the ligand activation profile of rabbit PXR is distinct from rat PXR and more closely resembles that of human PXR. The rabbit PXR activation profile is consistent with the cytochrome P450 (P450) 3A6 induction profile in rabbits.

Footnotes

  • Send reprint requests to: Eric F. Johnson, Division of Biochemistry, NX-4, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. E-mail: johnson{at}scripps.edu

  • ↵1 The GenBank accession number for the rabbit PXR nucleotide sequence is .

  • This work was funded by U.S. Public Health Service Grant HD04445. Facilities for computer-assisted sequence analysis, DNA sequencing, and the synthesis of oligonucleotides are supported in part by General Clinical Research Center Grant M01 RR00833 and by the Sam and Rose Stein Charitable Trust.

  • Abbreviations used are::
    P450
    cytochrome P450
    DEX
    dexamethasone
    PCN
    pregnenolone 16α-carbonitrile
    GR
    glucocorticoid receptor
    TAO
    troleandromycin
    DR3
    direct repeat separated by three nucleotides
    PXR
    pregnane X receptor
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    DBD
    DNA binding domain
    LBD
    ligand binding domain
    nt
    nucleotides
    bp
    base pairs
    RACE
    rapid amplification of cDNA ends
    DMSO
    dimethyl sulfoxide
    • Received September 2, 1999.
    • Accepted January 19, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (5)
Drug Metabolism and Disposition
Vol. 28, Issue 5
1 May 2000
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Research ArticleArticle

Rabbit Pregnane X Receptor Is Activated by Rifampicin

Üzen Savas, Michael R. Wester, Keith J. Griffin and Eric F. Johnson
Drug Metabolism and Disposition May 1, 2000, 28 (5) 529-537;

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Research ArticleArticle

Rabbit Pregnane X Receptor Is Activated by Rifampicin

Üzen Savas, Michael R. Wester, Keith J. Griffin and Eric F. Johnson
Drug Metabolism and Disposition May 1, 2000, 28 (5) 529-537;
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