PXR Alternative mRNAs

Alignment of all ests in GenBank revealed that there are a number of est transcripts that differ in the length of the amino terminal end. The primary transcript, in terms 

FIGURE 9.2 PXR has multiple isoforms with different amino terminal ends, (a) Amino acid alignment of PXR est isoforms. PXR is the most abundant isoform. (b) Generation of PXR, PAR.2, and PRR isoforms utilizing different initiation codons in exons la, lb, and 2. See color insert. 

Alternative splicing of hPXR (also referred to as hPXR.l) also gives rise to two additional hPXR transcripts in a variety of tissues [16, 25] PXR.2 (splice variant 2, S V2) has a 111 bp deletion at the 5 end of exon 5. This alternative PXR mRNA was originally detected in breast tissue and results in an in-frame deletion of 37 amino acids (174-210) from the LBD of PXR protein [26]. PXR.2 is produced by usage of a cryptic splice acceptor site within exon 5. Human PXR.3 (SV3) was identical to an 

The functional consequence of PXR.2 has been briefly examined in cell-based assays. Compared to PXR, PXR.2 had marked reduction of basal and ligand (rifampin and corticosterone) induced transactivation activity of a CYP3A4 reporter in LS174 T cells [18], and, similarly, the orthologous mouse isoform mPXR.2 showed reduced response to ligands compared to mPXR. 1 [27]. Likewise, some of the UGT1 As (PXR targets) were induced by rifampin in Caco-2 cells transfected with PXR. 1 and PAR.2, but not with hPXR.2 [31]. 

Fukuen et al. [25] identified seven additional splice variants of PXR in human liver. Seventy percent of the transcripts had an alteration in exon 5. However, they appear to be expressed at levels significantly lower than PXR or PXR.2 or PXR.3 and have not been functionally characterized. 

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