PXR and CAR single nucleotide polymorphisms influence plasma efavirenz levels in South African HIV/AIDS patients

<p>Abstract</p> <p>Background</p> <p>This study investigated variation in <it>NR1I2</it> and <it>NR1I3</it> and its effect on plasma efavirenz levels in HIV/AIDS patients. Variability in plasma drug levels has largely led research on identifying causative variants in drug metabolising enzyme (DME) genes, with little focus on the nuclear receptor genes <it>NR1I2</it> and <it>NR1I3</it>, coding for PXR and CAR, respectively, that are involved in regulating DMEs.</p> <p>Methods</p> <p>464 Bantu-speaking South Africans comprising of HIV/AIDS patients on efavirenz-based treatment (n=301) and 163 healthy subjects were genotyped for 6 SNPs in <it>NR1I2</it> and <it>NR1I3</it>. 32 of the 301 patients had their DNA binding domains (DBDs) in <it>NR1I2</it> and <it>NR1I3</it> sequenced.</p> <p>Results</p> <p>Significantly decreased efavirenz plasma concentrations were observed in patients carrying the <it>NR1I3 rs3003596C/C</it> and <it>T/C</it> genotypes (P=0.015 and P=0.010, respectively). Sequencing resulted in the discovery of a further 13 SNPs, 3 of which are novel variants in the DBD of <it>NR1I2</it>. There were significant differences in the distribution of <it>NR1I2</it> and <it>NR1I3</it> SNPs between South Africans when compared to Caucasian, Asian and Yoruba population groups.</p> <p>Conclusion</p> <p>For the realisation of personalised medicine, PXR and CAR genetic variation should be taken into consideration because of their involvement in the regulation of DMEs.</p

Elucidating the ‘Jekyll and Hyde’ Nature of PXR: The Case for Discovering Antagonists or Allosteric Antagonists

The pregnane X receptor belongs to the nuclear hormone receptor superfamily and is involved in the transcriptional control of numerous genes. It was originally thought that it was a xenobiotic sensor controlling detoxification pathways. Recent studies have shown an increasingly important role in inflammation and cancer, supporting its function in abrogating tissue damage. PXR orthologs and PXR-like pathways have been identified in several non-mammalian species which corroborate a conserved role for PXR in cellular detoxification. In summary, PXR has a multiplicity of roles in vivo and is being revealed as behaving like a “Jekyll and Hyde” nuclear hormone receptor. The importance of this review is to elucidate the need for discovery of antagonists of PXR to further probe its biology and therapeutic applications. Although several PXR agonists are already reported, virtually nothing is known about PXR antagonists. Here, we propose the development of PXR antagonists through chemical, genetic and molecular modeling approaches. Based on this review it will be clear that antagonists of PXR and PXR-like pathways will have widespread utility in PXR biology and therapeutics