Comparative genomics of xenobiotic metabolism: a porcine-human PXR gene comparison.

The pregnane X receptor (PXR) plays a crucial role in xenobiotic and drug metabolism, being the major transcriptional regulator of cytochrome P-450 monooxygenase 3A4, which metabolizes more than 50% of all clinically used drugs. Recent pharmacodynamic studies have shown that the mouse is not an ideal model for predicting human clinical drug study outcomes. Therefore, we characterized the porcine PXR (pPXR) gene to evaluate the utility of the pig as an alternate preclinical animal model. The complete sequence of pPXR mRNA and 11 kb of genomic sequence were obtained. Similar to the human PXR gene, the pPXR gene revealed multiple splice variants in the ligand-binding domain. All pPXR splice variants (SV) were porcine-specific. The pPXR mRNAs varied in 3'-UTR length due to differential termination and specific deletions. Northern blot analyses identified high levels of pPXR mRNA expression in the liver, small intestine, heart, kidney, and colon. RT-PCR amplification detected lower levels of pPXR expression in multiple tissues. Ninety-three pigs representing eight breeds were analyzed for single nucleotide polymorphisms (SNPs). Only one nonsynonymous SNP (S178L) was found in the pPXR ligand-binding domain. This characterization of the pPXR gene contributes to the development of a porcine model for human drug metabolic studies.

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