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Vol. 28, Issue 5, 529-537, May 2000
Department of Molecular and Experimental Medicine, The Scripps
Research Institute, La Jolla, California
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 
ZAP
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 16
-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.
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