The ATP-binding cassette transporter G2 (ABCG2; also known as breast cancer resistance protein, BCRP) has been suggested to be involved in clinical multidrug resistance (MDR) in cancer like other ABC transporters such as ABCB1 (P-glycoprotein). As an efflux pump exhibiting a broad substrate specificity localized on cellular plasma membrane, ABCG2 excretes a variety of endogenous and exogenous substrates including chemotherapeutic agents, such as mitoxantrone and several tyrosine kinase inhibitors. Moreover, in the normal tissues, ABCG2 is expressed on the apical membranes and plays a pivotal role in tissue protection against various xenobiotics. For this reason, ABCG2 is recognized to be an important determinant of the pharmacokinetic characteristics of its substrate drugs. Although the clinical relevance of reversing the ABCG2-mediated MDR has been inconclusive, an appropriate modulation of ABCG2 function during chemotherapy should logically enhance the efficacy of anti-cancer agents by overcoming the MDR phenotype and/or improving their pharmacokinetics. To confirm this possibility, considerable efforts have been devoted to developing ABCG2 inhibitors, although there is no clinically available substance for this purpose. As a clue for addressing this issue, this mini-review provides integrated information covering the technical backgrounds necessary to evaluate the ABCG2 inhibitory effects on the target compounds and a current update on the ABCG2 inhibitors. This essentially includes our recent findings, as we serendipitously identified febuxostat, a well-used agent for hyperuricemia as a strong ABCG2 inhibitor, that possesses some promising potentials. We hope that an overview described here will add value to further studies involving in the multidrug transporters.

Objective A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. Methods Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. Results In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10⁻⁸): urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (p_meta=3.58×10⁻⁸). Conclusions Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.

ATP-binding cassette transporter G2 (ABCG2) is a plasma membrane protein that regulates the pharmacokinetics of a variety of drugs and serum uric acid (SUA) levels in humans. Despite the pharmacological and physiological importance of this transporter, there is no clinically available drug that modulates ABCG2 function. Therefore, to identify such drugs, we investigated the effect of drugs that affect SUA levels on ABCG2 function. This strategy was based on the hypothesis that the changes of SUA levels might caused by interaction with ABCG2 since it is a physiologically important urate transporter. The results of the in vitro screening showed that 10 of 25 drugs investigated strongly inhibited the urate transport activity of ABCG2. Moreover, febuxostat was revealed to be the most promising candidate of all the potential ABCG2 inhibitors based on its potent inhibition at clinical concentrations; the half-maximal inhibitory concentration of febuxostat was lower than its maximum plasma unbound concentrations reported. Indeed, our in vivo study demonstrated that orally administered febuxostat inhibited the intestinal Abcg2 and, thereby, increased the intestinal absorption of an ABCG2 substrate sulfasalazine in wild-type mice, but not in Abcg2 knockout mice. These results suggest that febuxostat might inhibit human ABCG2 at a clinical dose. Furthermore, the results of this study lead to a proposed new application of febuxostat for enhancing the bioavailability of ABCG2 substrate drugs, named febuxostat-boosted therapy, and also imply the potential risk of adverse effects by drug-drug interactions that could occur between febuxostat and ABCG2 substrate drugs.

1. The adenosine triphosphate (ATP) binding cassette (ABC) transporters form one of the largest protein families encoded in the human genome, and more than 48 genes encoding human ABC transporters have been identified and sequenced. It has been reported that mutations of ABC protein genes are causative in several genetic disorders in humans. 2. Many human ABC transporters are involved in membrane transport of drugs, xenobiotics, endogenous substances or ions, thereby exhibiting a wide spectrum of biological functions. According to the new nomenclature of human ABC transporter genes, the 'ABCC' gene sub-family comprises three classes involving multidrug resistance-associated proteins (MRPs), sulfonylurea receptors (SURs), and a cystic fibrosis transmembrane conductance regulator (CFTR). 3. Molecular cloning studies have identified a total of ten members of the human MRP class including ABCC11, ABCC12, and ABCC13 (pseudo-gene) that have recently been characterized. 4. This review addresses the historical background and discovery of the ATP-driven xenobiotic export pumps (GS-X pumps) encoded by MRP genes, biological functions of ABC transporters belonging to the MRP class, and regulation of gene expression of MRPs by oxidative stress.

Vitamin K (VK) is a micronutrient that facilitates blood coagulation. VK antagonists, such as warfarin, are used in the clinic to prevent thromboembolism. Because VK is not synthesized in the body, its intestinal absorption is crucial for maintaining whole-body VK levels. However, the molecular mechanism of this absorption is unclear. We demonstrate that Niemann-Pick C1-like 1 (NPC1L1) protein, a cholesterol transporter, plays a central role in intestinal VK uptake and modulates the anticoagulant effect of warfarin. In vitro studies using NPC1L1-overexpressing intestinal cells and in vivo studies with Npc1l1-knockout mice revealed that intestinal VK absorption is NPC1L1-dependent and inhibited by ezetimibe, an NPC1L1-selective inhibitor clinically used for dyslipidemia. In addition, in vivo pharmacological studies demonstrated that the coadministration of ezetimibe and warfarin caused a reduction in hepatic VK levels and enhanced the pharmacological effect of warfarin. Adverse events caused by the coadministration of ezetimibe and warfarin were rescued by oral VK supplementation, suggesting that the drug-drug interaction effects observed were the consequence of ezetimibe-mediated VK malabsorption. This mechanism was supported by a retrospective evaluation of clinical data showing that, in more than 85% of warfarin-treated patients, the anticoagulant activity was enhanced by cotreatment with ezetimibe. Our findings provide insight into the molecular mechanism of VK absorption. This new drug-drug interaction mechanism between ezetimibe (a cholesterol transport inhibitor) and warfarin (a VK antagonist and anticoagulant) could inform clinical care of patients on these medications, such as by altering the kinetics of essential, fat-soluble vitamins.