Hepatic OATP1B Transporters and Nuclear Receptors PXR and CAR: Interplay, Regulation of Drug Disposition Genes, and Single Nucleotide Polymorphisms

Abstract

Drug uptake transporters are now increasingly recognized as clinically relevant determinants of variable drug responsiveness and unexpected drug-drug interactions. Emerging evidence strongly suggests members of the organic anion transporting polypeptide (OATP) family appear to be particularly important to the disposition of many drugs in clinical use today. Specifically, the liver-enriched OATP1B subfamily members OATP1B1 and OATP1B3 exhibit broad substrate specificity and the ability to transport drugs which are ligands for xenobiotic sensing nuclear receptors such as the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Accordingly, OATP1B transporters may indirectly regulate expression of drug metabolism genes via modulation of the intracellular concentration of PXR and CAR ligands. Moreover, a number of functionally important single nucleotide polymorphisms (SNPs) in OATP1B transporters have been described. In this review, a brief summary of known SNPs in PXR and CAR will be followed by an in-depth outline of OATP1B1 and OATP1B3 transporters particularly in relation to the known SNPs in these OATPs and the interplay between OATP1B transporters with PXR and CAR, both in vitro and in vivo.

Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort

“…Importantly, there was no difference in the c.521C allele frequency (0.17) in this subgroup compared with previously published frequencies in a White population (0.14) [23] or the frequency in the rest of the SHIP population. Similarly, the frequency of the 388G allele was comparable to those reported previously (0.39 compared with published 0.30) [23]. At baseline, there was no association of the SLCO1B1 c.521T > C genotype with LDL or TC plasma levels, respectively, either in patients with isolated hypercholesterolaemia (mean SD LDL-cholesterol, SLCO1B1 c. As mentioned before, a total of 214 individuals were summarized in the statin therapy group for statistical analysis (Fig.…”

“…We determined the influence of OATP1B1 variants on nonfasting lipid parameters in the subpopulation with dyslipoproteinaemia according to the ATPIII guidelines [18]. Importantly, there was no difference in the c.521C allele frequency (0.17) in this subgroup compared with previously published frequencies in a White population (0.14) [23] or the frequency in the rest of the SHIP population. Similarly, the frequency of the 388G allele was comparable to those reported previously (0.39 compared with published 0.30) [23].…”

Integrating pharmacogenetics and therapeutic drug monitoring: optimal dosing of imatinib as a case-example

“…However, to date, none of the studied CYP450 metabolic enzyme genotypes have shown sufficiently strong predictive power to be useful for imatinib dose-blood level prediction in clinical practice [30] when assessed using methodology we have described elsewhere for other types of genetic testing for both prognostic purposes [31] and critical evaluation of the impact of new variants [32]. This may be due to the complex interactions in the expression of the CYP450 enzymes [33][34][35], including epigenetic effects, the participation of microRNAs [36] and their polymorphisms [37] and the interplay between transporters and metabolic enzymes, which has yet to be fully unravelled [38].…”

Role of NR1I2 (pregnane X receptor) polymorphisms in head and neck squamous cell carcinoma

“…In vitro, PXR is dysfunctional in HNSCC, because even the prototype activator of PXR rifampicin failed to enhance PXR activity in the majority of HNSCC cell lines tested (Rigalli et al 2013). So far, the underlying molecular reason is unclear, but inactivating single nucleotide polymorphisms (SNPs) within the NR1I2 gene encoding PXR is one possible reason, because NR1I2 SNPs can modulate PXR expression, inducibility, and cancer pathogenesis as demonstrated in several other tissues (Zhang et al 2008;Kotta-Loizou et al 2013;Meyer zu Schwabedissen and Kim 2009). For instance, some silent SNPs in intronic regions of NR1I2 are associated with the variability of the CYP3A4 expression subsequent to PXR activation by rifampicin, indicating an impact of NR1I2 polymorphisms on inducibility by PXR (Zhang et al 2001).…”