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 (
-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.
Human ATP-binding cassette transporter C11 (ABCC11) is a membrane protein exhibiting ATP-dependent transport activity for a variety of lipophilic anions including endogenous substances and ...xenobiotics such as anti-cancer agents. Accumulating evidence indicates that ABCC11 wild type is responsible for the high-secretion phenotypes in human apocrine glands including wet type of earwax and the risk of axillary osmidrosis. Also, a less-functional variant of ABCC11 was reportedly associated with a risk for drug-induced toxicity in humans. Thus, functional change in ABCC11 may affect individual’s constitution and drug toxicity, which led us to reason that functional validation of genetic variations in
ABCC11
should be of importance. Therefore, in addition to p.G180R (a well-characterized non-functional variant of ABCC11), we studied cellular expression and function of 10 variants of ABCC11. In this study, ABCC11 function was evaluated as an ATP-dependent transport of radio labeled-dehydroepiandrosterone sulfate using ABCC11-expressing plasma membrane vesicles. Except for p.G180R, other 10 variants were maturated as an
N
-linked glycoprotein and expressed on the plasma membrane. We found that six variants impaired the net cellular function of ABCC11. Among them, p.R630W was most influential. Including this identification of a significantly-dysfunctional variant, our findings will extend our understanding of genetic variations and biochemical features of ABCC11 protein.
Indoxyl sulfate (IS) accumulates in the body in chronic kidney disease (CKD). In the renal proximal tubules, IS excretion is mediated by OAT1/3 and ABCG2. These transporters are inhibited by some ...hypouricemic agents; OATs by probenecid and benzbromarone, ABCG2 by febuxostat and benzbromarone. Thus, we evaluated whether hypouricemic agents including dotinurad, a novel selective urate reabsorption inhibitor with minimal effect on OATs or ABCG2, affect IS clearance in rats. Intact and adenine-induced acute renal failure rats were orally administered hypouricemic agents, and both endogenous IS and exogenously administered stable isotope-labeled d
-IS in the plasma and kidney were measured. Our results demonstrated that OATs inhibitors, such as probenecid, suppress IS uptake into the kidney, leading to increased plasma IS concentration, whereas ABCG2 inhibitors, such as febuxostat, cause renal IS accumulation remarkably by suppressing its excretion in intact rats. The effects of these agents were reduced in adenine-induced acute renal failure rats, presumably due to substantial decrease in renal OAT1/3 and ABCG2 expression. Dotinurad did not significantly affected the clearance of IS under both conditions. Therefore, we suggest that hypouricemic agents that do not affect OATs and ABCG2 are effective therapeutic options for the treatment of hyperuricemia complicated by CKD.
Westernization of dietary habits leads to an increase in lipid intake and is thought to be responsible for an increase in patients with dyslipidemia. It is a well-known fact that the impaired ...cholesterol homeostasis is closely related to the development of various lifestyle-related diseases such as fatty liver, diabetes, and gallstone as well as dyslipidemia leading to atherosclerosis and cardiovascular diseases such as heart attack and stroke. Therefore, appropriate management of cholesterol levels in the body is considered important in prevention and treatments of these lifestyle-related diseases and in addition, molecular mechanisms controlling plasma (and/or hepatic) cholesterol levels have been intensively studied. Due to its hydrophobicity, cholesterol was long believed to pass through cell membranes by passive diffusion. However, recent studies have identified a number of plasma membrane transporters that are responsible for the cellular uptake or efflux of cholesterol and involved in developments of lifestyle-related diseases. In this review, we focus on Niemann–Pick C1 Like 1 (NPC1L1) and a heterodimer of ATP-binding cassette transporter G5 and G8 (ABCG5/G8), both of which are responsible for intestinal cholesterol absorption and biliary cholesterol secretion, and discuss the relationship between these cholesterol transporters and lifestyle-related diseases. In addition, we also discuss the related uncertainties that need to be explored in future studies.
Humans cannot synthesize fat-soluble vitamins such as vitamin E and vitamin K. For this reason, they must be obtained from the diet via intestinal absorption. As the deficiency or excess of these ...vitamins has been reported to cause several types of diseases and disorders in humans, the intestinal absorption of these nutrients must be properly regulated to ensure good health. However, the mechanism of their intestinal absorption remains poorly understood. Recent studies on cholesterol using genome-edited mice, genome-wide association approaches, gene mutation analyses, and the development of cholesterol absorption inhibitors have revealed that several membrane proteins play crucial roles in the intestinal absorption of cholesterol. Surprisingly, detailed analyses of these cholesterol transporters have revealed that they can also transport vitamin E and vitamin K, providing clues to uncover the molecular mechanisms underlying the intestinal absorption of these fat-soluble vitamins. In this review, we focus on the membrane proteins (Niemann-Pick C1 like 1, scavenger receptor class B type I, cluster of differentiation 36, and ATP-binding cassette transporter A1) that are (potentially) involved in the intestinal absorption of cholesterol, vitamin E, and vitamin K and discuss their physiological and pharmacological importance. We also discuss the related uncertainties that need to be explored in future studies.
ATP-binding cassette protein G5 (ABCG5)/ABCG8 heterodimer exports cholesterol from cells, while Niemann-Pick C1-like 1 (NPC1L1) imports cholesterol and vitamin K. We examined whether ABCG5/ABCG8 ...transports vitamin K similar to NPC1L1. Since high concentrations of vitamin K
show cytotoxicity, the cytoprotective effects of ABCG5/ABCG8 were examined. BHK cells expressing ABCG5/ABCG8 were more resistant to vitamin K
cytotoxicity than control cells, suggesting that ABCG5/ABCG8 transports vitamin K
out of cells. The addition of vitamin K
reversed the effects of ABCG5/ABCG8, suggesting that vitamin K
competitively inhibits the transport of vitamin K
. To examine the transport of vitamin K
by ABCG5/ABCG8, vitamin K
levels in the medium and cells were measured. Vitamin K
levels in cells expressing ABCG5/ABCG8 were lower than those in control cells, while vitamin K
efflux increased in cells expressing ABCG5/ABCG8. Furthermore, the biliary vitamin K
concentration in Abcg5/Abcg8-deficient mice was lower than that in wild-type mice, although serum vitamin K
levels were not affected by the presence of Abcg5/Abcg8. These findings suggest that ABCG5 and ABCG8 are involved in the transport of sterols and vitamin K. ABCG5/ABCG8 and NPC1L1 might play important roles in the regulation of vitamin K absorption and excretion.
ABCG2, also known as BCRP, is a high-capacity urate exporter, the dysfunction of which raises gout/hyperuricemia risk. Generally, hyperuricemia has been classified into urate 'overproduction type' ...and/or 'underexcretion type' based solely on renal urate excretion, without considering an extra-renal pathway. Here we show that decreased extra-renal urate excretion caused by ABCG2 dysfunction is a common mechanism of hyperuricemia. Clinical parameters, including urinary urate excretion, are examined in 644 male outpatients with hyperuricemia. Paradoxically, ABCG2 export dysfunction significantly increases urinary urate excretion and risk ratio of urate overproduction. Abcg2-knockout mice show increased serum uric acid levels and renal urate excretion, and decreased intestinal urate excretion. Together with high ABCG2 expression in extra-renal tissues, our data suggest that the 'overproduction type' in the current concept of hyperuricemia be renamed 'renal overload type', which consists of two subtypes-'extra-renal urate underexcretion' and genuine 'urate overproduction'-providing a new concept valuable for the treatment of hyperuricemia and gout.
Abstract
Objectives
Limited evidence is available regarding alternative therapeutic agents to vancomycin in treating glycopeptide-susceptible Enterococcus faecium (GSEF) bacteraemia. This study ...assessed the effectiveness and safety of teicoplanin compared with vancomycin for treating GSEF bacteraemia.
Patients and methods
This was a retrospective, non-inferiority cohort study. Patients aged ≥18 years who developed GSEF bacteraemia and received either teicoplanin or vancomycin were included. The primary effectiveness outcome was the clinical success at the end of treatment, with a generalized linear model using the propensity score for selecting the agent as a covariate. We used an absolute difference of 20% in clinical success as the non-inferiority margin. Using multivariable logistic regression, the primary safety outcome was the incidence of acute kidney injury (AKI).
Results
In total, 164 patients (74 and 90 in the teicoplanin and vancomycin groups, respectively) were included. Overall, 64.9% (48/74) and 48.9% (44/90) of patients in the teicoplanin and vancomycin groups, respectively, achieved the primary effectiveness outcome. A generalized linear analysis showed an adjusted effectiveness difference of 9.9% (95% CI, −0.9% to 20.0%; P = 0.07), indicating non-inferiority of teicoplanin versus vancomycin. The incidence of AKI was 8.1% (6/74) and 24.4% (22/90) in the teicoplanin and vancomycin groups, respectively, with an adjusted OR of 0.242 (95% CI, 0.068 to 0.864; P = 0.029), indicating significantly lower AKI risk in the teicoplanin than in the vancomycin group.
Conclusions
Teicoplanin is a safe and useful alternative therapeutic agent for treating GSEF bacteraemia.
Weekly paclitaxel + ramucirumab (wPTX + RAM) therapy is recommended as the standard second-line chemotherapy regimen for unresectable advanced/recurrent gastric cancer (GC) or esophagogastric ...junction cancer. Recent subgroup analysis of the RAINBOW trial revealed a higher frequency of severe neutropenia due to wPTX + RAM in Japanese compared to Western patients. However, no risk factors for severe neutropenia have been identified.
This retrospective observational study included patients with advanced/unresectable gastric or esophagogastric junction cancer who received wPTX + RAM after failure to respond to platinum and fluoropyrimidine doublet chemotherapy between June 2015 and April 2020. We conducted multivariable logistic regression analyses to identify the risk factors associated with grade 4 neutropenia and febrile neutropenia (FN). In addition, we investigated the relationship between the number of risk factors and overall survival (OS) and progression-free survival (PFS).
Among 66 patients who met the inclusion criteria, grade 4 neutropenia and FN occurred in 21 (31.8%) and 12 (18.2%) patients, respectively. Prior treatment with oxaliplatin-containing regimens was identified as an independent risk factor for developing grade 4 neutropenia (odds ratio (OR) 20.034, 95% confidence interval (95% CI) 3.216-124.807, P = 0.001). Total bilirubin of > 1.5 mg/dL (OR 31.316, 95% CI 2.052-477.843, P = 0.013) and prior treatment with oxaliplatin-containing regimen (OR 12.502, 95% CI 1.141-137.022, P = 0.039) were identified as independent risk factors for developing FN. Next, we classified patients with 0, 1, 2 risk factor(s) as RF-0, RF-1, and RF-2 subgroups, respectively, and compared the PFS and OS among the three subgroups. PFS was not significantly different among the three subgroups, whereas OS was significantly shorter in the RF-2 subgroup (median 1.4 month, 95% CI 0.0-5.3 month) than in the RF-0 subgroup (median 10.2 month, 95% CI 6.8-13.5 month, P < 0.01 vs RF-2) and RF-1 subgroup (median 13.3 month, 95% CI 10.9-15.7 month, P < 0.01 vs RF-2).
Careful monitoring for grade 4 neutropenia and FN is needed for patients receiving wPTX + RAM therapy who have a history of treatment with oxaliplatin-containing regimens and higher total bilirubin levels.
PDF
