1. Purine cyclin-dependent kinase inhibitors have recently been recognised as promising candidates for the treatment of various cancers. While pharmacodynamic properties of these compounds are relatively well understood, their pharmacokinetics including possible interactions with placental transport systems have not been characterised to date. 2. In this study, we investigated transplacental passage of olomoucine II and purvalanol A in rat focusing on possible role of p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and/or multidrug resistance-associated proteins (ABCCs). Employing the in situ method of dually perfused rat term placenta, we demonstrate transplacental passage of both olomoucine II and purvalanol A against the concentration gradient in foetus-to-mother direction. Using several ATP-binding cassette (ABC) drug transporter inhibitors, we confirm the participation of ABCB1, ABCG2 and ABCCs transporters in the placental passage of olomoucine II, but not purvalanol A. 3. Transplacental passage of olomoucine II and purvalanol A from mother to foetus is significantly reduced by active transporters, restricting thereby foetal exposure and providing protection against harmful effects of these xenobiotics. Importantly, we demonstrate that in spite of their considerable structural similarity, the two molecules utilise distinct placental transport systems. These facts should be kept in mind when introducing these prospective anticancer candidates and/or their analogues into the clinical area.

• Klíčová slova
• Cyclin-dependent kinase inhibitors, drug efflux transporters, olomoucine II, placental pharmacokinetics, purvalanol A,
• MeSH
• ABC transportér z rodiny G, člen 2 MeSH
• ABC transportéry metabolismus   MeSH
• adenosintrifosfát chemie   MeSH
• aktivní transport MeSH
• krysa rodu Rattus MeSH
• matka - expozice noxám MeSH
• P-glykoproteiny metabolismus   MeSH
• placenta účinky léků   metabolismus   MeSH
• potkani Wistar MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům metabolismus   MeSH
• puriny aplikace a dávkování   farmakokinetika   MeSH
• roskovitin MeSH
• těhotenství u zvířat MeSH
• těhotenství MeSH
• trofoblasty účinky léků   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• xenobiotika chemie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine MeSH Prohlížeč
• ABC transportér z rodiny G, člen 2 MeSH
• ABC transportéry MeSH
• Abcg2 protein, rat MeSH Prohlížeč
• adenosintrifosfát MeSH
• multidrug resistance protein 3 MeSH Prohlížeč
• olomoucine II MeSH Prohlížeč
• P-glykoproteiny MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH
• puriny MeSH
• roskovitin MeSH
• xenobiotika MeSH

BACKGROUND: Adaptive response to hypoxia is regulated by several mechanisms and transcription factors, including hypoxia-inducible factors (HIFs). Activation of HIF-1α is associated with increased expression of P-glycoprotein and multidrug resistance in cancer cells. In this retrospective study, we analyzed candidate single-nucleotide polymorphisms (SNPs) in HIF-1α and HIF-1β associated with risk of monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM). PATIENTS AND METHODS: Genotypes of SNPs associated with hypoxia were determined in an independent cohort of monoclonal gammopathies (MG) (275 MM and 228 MGUS patients) and in 219 cancer-free controls by real time polymerase chain reaction allelic discrimination. RESULTS: When MM patients were compared to controls, protective role of CG genotype compared to CC in HIF-1β (rs2228099) for MM development was observed (OR = 0.65; CI 0.45-0.95; p = 0.026). Even after adjustment for patients' age and body mass index (BMI), there were significantly lower odds (OR = 0.55; p = 0.045) of developing MM patients of CG genotype in comparison to CC genotype. Log-rank test confirmed association of GT haplotype (rs11549467, rs2057482) in HIF-1α with better overall survival (median 41.8 months; (CI 35.1-48.5)) for "none GT" and median 93.8 months (CI 31.3-156.4) for "at least one GT" haplotype (p = 0.0500). Further, significant associations between SNPs in MDR1 and outcome of MM were found in 110 MM patients that underwent bortezomib-based treatment. CONCLUSION: Our study showed a genetic predisposition for risk of MG development and/or outcome of MM patients; nevertheless, further studies are needed to confirm our initial analysis.

• Klíčová slova
• multiple myeloma - hypoxia - genotype - polymorphism - qPCR.,
• MeSH
• doba přežití bez progrese choroby MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa genetika   MeSH
• genetická predispozice k nemoci MeSH
• hypoxie genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetná léková rezistence genetika   MeSH
• P-glykoproteiny genetika   MeSH
• paraproteinemie genetika   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   MeSH
• receptory aromatických uhlovodíků - jaderný translokátor genetika   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABCB1 protein, human MeSH Prohlížeč
• ARNT protein, human MeSH Prohlížeč
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• HIF1A protein, human MeSH Prohlížeč
• multidrug resistance-associated protein 1 MeSH Prohlížeč
• P-glykoproteiny MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH
• receptory aromatických uhlovodíků - jaderný translokátor MeSH

Methyl mercury (MeHg) is an organic highly toxic compound that is transported efficiently via the human placenta. Our previous data suggest that MeHg is taken up into placental cells by amino acid transporters while mercury export from placental cells mainly involves ATP binding cassette (ABC) transporters. We hypothesized that the ABC transporter multidrug resistance-associated protein (MRP)1 (ABCC1) plays an essential role in mercury export from the human placenta. Transwell transport studies with MRP1-overexpressing Madin-Darby Canine Kidney (MDCK)II cells confirmed the function of MRP1 in polarized mercury efflux. Consistent with this, siRNA-mediated MRP1 gene knockdown in the human placental cell line HTR-8/SVneo resulted in intracellular mercury accumulation, which was associated with reduced cell viability, accompanied by increased cytotoxicity, apoptosis, and oxidative stress as determined via the glutathione (GSH) status. In addition, the many sources claiming different localization of MRP1 in the placenta required a re-evaluation of its localization in placental tissue sections by immunofluorescence microscopy using an MRP1-specific antibody that was validated in-house. Taken together, our results show that (1) MRP1 preferentially mediates apical-to-basolateral mercury transport in epithelial cells, (2) MRP1 regulates the GSH status of placental cells, (3) MRP1 function has a decisive influence on the viability of placental cells exposed to low MeHg concentrations, and (4) the in situ localization of MRP1 corresponds to mercury transport from maternal circulation to the placenta and fetus. We conclude that MRP1 protects placental cells from MeHg-induced oxidative stress by exporting the toxic metal and by maintaining the placental cells' GSH status in equilibrium.

• Klíčová slova
• HTR-8/SVneo, Human placenta, MDCKII, Methyl mercury, Multidrug resistance-associated protein 1, Oxidative stress,
• MeSH
• ABC transportéry metabolismus   MeSH
• apoptóza účinky léků   MeSH
• buněčné linie MeSH
• buňky MDCK MeSH
• endoteliální buňky MeSH
• genový knockdown MeSH
• glutathion metabolismus   MeSH
• imunohistochemie MeSH
• kultivované buňky MeSH
• lidé MeSH
• methylortuťné sloučeniny škodlivé účinky   metabolismus   MeSH
• oxidační stres * MeSH
• placenta metabolismus   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům fyziologie   MeSH
• psi MeSH
• těhotenství MeSH
• transportní systémy aminokyselin metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• psi MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABC transportéry MeSH
• dimethyl mercury MeSH Prohlížeč
• glutathion MeSH
• methylortuťné sloučeniny MeSH
• multidrug resistance-associated protein 1 MeSH Prohlížeč
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH
• transportní systémy aminokyselin MeSH

Abacavir is as a frequent part of combination antiretroviral therapy used in pregnant women. The aim of this study was to investigate, using in vitro, in situ and ex vivo experimental approaches, whether the transplacental pharmacokinetics of abacavir is affected by ATP-binding cassette (ABC) efflux transporters functionally expressed in the placenta: P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), multidrug resistance-associated protein 2 (ABCC2) and multidrug resistance-associated protein 5 (ABCC5). In vitro transport assays revealed that abacavir is a substrate of human ABCB1 and ABCG2 transporters but not of ABCC2 or ABCC5. In addition, in situ experiments using dually perfused rat term placenta confirmed interactions of abacavir with placental Abcb1/Abcg2. In contrast, uptake studies in human placental villous fragments did not reveal any interaction of abacavir with efflux transporters suggesting a large contribution of passive diffusion and/or influx mechanisms to net transplacental abacavir transfer.

• Klíčová slova
• Abacavir, Breast cancer resistance protein, HIV, Multidrug resistance-associated proteins, P-glycoprotein, Transplacental pharmacokinetics,
• MeSH
• antiretrovirové látky farmakokinetika   MeSH
• buňky MDCK MeSH
• dideoxynukleosidy farmakokinetika   MeSH
• lidé MeSH
• placenta metabolismus   MeSH
• potkani Wistar MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům metabolismus   MeSH
• psi MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• psi MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• abacavir MeSH Prohlížeč
• ABCC2 protein, human MeSH Prohlížeč
• antiretrovirové látky MeSH
• dideoxynukleosidy MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH

Zidovudine (AZT) is one of the most frequently used antiretroviral drugs in prevention of perinatal transmission of HIV. However, safety concerns on AZT use in pregnancy still persist as severe side effects are associated with AZT exposure in children. In our study we aimed to contribute to current knowledge on AZT transplacental transport and to evaluate potential involvement of the main human drug efflux ATP-binding cassette (ABC) transporters, p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and multidrug resistance-associated proteins 2 and 5 (ABCC2 and ABCC5) in the disposition of AZT between mother and fetus. In order to elucidate this issue we investigated the effect of selected ABC transporters on AZT transepithelial transport across MDCKII cell monolayers. In addition we used the in situ method of dually perfused rat term placenta to further study the role of ABC transporters in AZT transplacental transport. In vitro studies revealed significant effect of ABCB1 and ABCG2 on AZT transport which was subsequently confirmed also on organ level. Lamivudine, an antiretroviral agent commonly co-administered with AZT, did not affect ABC transporter-mediated AZT transfer.

• Klíčová slova
• breast cancer resistance protein, multidrug resistance-associated protein 2, multidrug resistance-associated protein 5, p-glycoprotein, zidovudine,
• MeSH
• ABC transportéry antagonisté a inhibitory   metabolismus   MeSH
• akridiny farmakologie   MeSH
• buňky MDCK MeSH
• indomethacin farmakologie   MeSH
• lamivudin farmakologie   MeSH
• látky proti HIV farmakokinetika   MeSH
• lékové interakce MeSH
• placenta metabolismus   MeSH
• potkani Wistar MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• psi MeSH
• techniky in vitro MeSH
• těhotenství MeSH
• tetrahydroisochinoliny farmakologie   MeSH
• zidovudin farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• psi MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABC transportéry MeSH
• ABCC2 protein, human MeSH Prohlížeč
• akridiny MeSH
• Elacridar MeSH Prohlížeč
• indomethacin MeSH
• lamivudin MeSH
• látky proti HIV MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• tetrahydroisochinoliny MeSH
• zidovudin MeSH

ATP-binding cassette (ABC) and solute carrier (SLC) transporters translocate diverse substances across cellular membranes and their deregulation may cause drug resistance of cancers. This study investigated significance of protein expression and cellular localization of the previously suggested putative prognostic markers ABCC2 and SLC22A3 in pancreatic cancer patients. Protein localization and brush border staining intensity of ABCC2 and SLC22A3 was assessed in tumor tissue blocks of 65 pancreatic cancer patients and associated with clinical data and survival of patients with regard to therapy. Negative SLC22A3 brush border staining in pancreatic tumors significantly increased the risk of both disease progression and patient´s death in univariate analyses. Multivariate analyses confirmed the association of SLC22A3 expression with progression-free survival of patients. A subgroup analysis of patients treated with regimens based on nucleoside analogs suggested that patients with negative brush border staining or apical localization of SLC22A3 in tumor cells have worse overall survival. The combination of positive ABCC2 and negative SLC22A3 brush border staining predicted worst overall survival and patients with positive brush border staining of both proteins had best overall and progression-free survival. The present study shows for the first time that the protein presence and to some extent also localization of SLC22A3 significantly associate with prognosis of pancreatic cancer in both unstratified and chemotherapy-treated patients. The combination of ABCC2 and SLC22A3 brush border staining also needs further attention in this regard.

• MeSH
• adenokarcinom * metabolismus   mortalita   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• nádorové proteiny biosyntéza   MeSH
• nádory slinivky břišní * metabolismus   mortalita   patologie   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny přenášející organické kationty biosyntéza   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům biosyntéza   MeSH
• regulace genové exprese u nádorů * MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABCC2 protein, human MeSH Prohlížeč
• nádorové proteiny MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny přenášející organické kationty MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH
• solute carrier family 22 (organic cation transporter), member 3 MeSH Prohlížeč

Multidrug resistance-associated protein 2 (Mrp2) mediates biliary secretion of anionic endobiotics and xenobiotics. Genetic alteration of Mrp2 leads to conjugated hyperbilirubinemia and predisposes to the development of intrahepatic cholestasis of pregnancy (ICP), characterized by increased plasma bile acids (BAs) due to mechanisms that are incompletely understood. Therefore, this study aimed to characterize BA metabolomics during experimental Mrp2 deficiency and ICP. ICP was modeled by ethinylestradiol (EE) administration to Mrp2-deficient (TR) rats and their wild-type (WT) controls. Spectra of BAs were analyzed in plasma, bile, and stool using an advanced liquid chromatography-mass spectrometry (LC-MS) method. Changes in BA-related genes and proteins were analyzed in the liver and intestine. Vehicle-administered TR rats demonstrated higher plasma BA concentrations consistent with reduced BA biliary secretion and increased BA efflux from hepatocytes to blood via upregulated multidrug resistance-associated protein 3 (Mrp3) and multidrug resistance-associated protein 4 (Mrp4) transporters. TR rats also showed a decrease in intestinal BA reabsorption due to reduced ileal sodium/bile acid cotransporter (Asbt) expression. Analysis of regulatory mechanisms indicated that activation of the hepatic constitutive androstane receptor (CAR)-Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by accumulating bilirubin may be responsible for changes in BA metabolomics in TR rats. Ethinylestradiol administration to TR rats further increased plasma BA concentrations as a result of reduced BA uptake and increased efflux via reduced Slco1a1 and upregulated Mrp4 transporters. These results demonstrate that Mrp2-deficient organism is more sensitive to estrogen-induced cholestasis. Inherited deficiency in Mrp2 is associated with activation of Mrp3 and Mrp4 proteins, which is further accentuated by increased estrogen. Bile acid monitoring is therefore highly desirable in pregnant women with conjugated hyperbilirubinemia for early detection of intrahepatic cholestasis.

• Klíčová slova
• Mrp2-deficient rats, Nrf2, bile acids, cholestasis, estrogen,
• Publikační typ
• časopisecké články MeSH

Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor used in first-line combination antiretroviral therapy (cART). It is usually administered with nucleoside reverse transcriptase inhibitors (NRTI), many of which are substrates of OCT uptake solute carriers (SLC22A) and MATE (SLC47A), P-gp (MDR1, ABCB1), BCRP (ABCG2), or MRP2 (ABCC2) efflux transporters. The aim of this study was to evaluate the inhibitory potential of efavirenz towards these transporters and investigate its effects on the pharmacokinetics and tissue distribution of a known Oct/Mate substrate, lamivudine, in rats. Accumulation and transport assays showed that efavirenz inhibits the uptake of metformin by OCT1-, OCT2- and MATE1-expressing MDCK cells and reduces transcellular transport of lamivudine across OCT1/OCT2- and MATE1-expressing MDCK monolayers. Only negligible inhibition of MATE2-K was observed in HEK-MATE2-K cells. Efavirenz also reduced the efflux of calcein from MDCK-MRP2 cells, but had a rather weak inhibitory effect on Hoechst 33342 accumulation in MDCK-MDR1 and MDCK-BCRP cells. An in vivo pharmacokinetic interaction study in male Wistar rats revealed that intravenous injection of efavirenz or the control Oct/Mate inhibitor cimetidine significantly reduced the recovery of lamivudine in urine and greatly increased lamivudine retention in the renal tissue. Co-administration with efavirenz or cimetidine also increased the AUC0-∞ value and reduced total body clearance of lamivudine. These data suggest that efavirenz is a potent inhibitor of OCT/Oct and MATE/Mate transporters. Consequently, it can engage in drug-drug interactions that reduce renal excretion of co-administered substrates and enhance their retention in the kidneys, potentially compromising therapeutic safety.

• MeSH
• alkyny MeSH
• benzoxaziny farmakologie   MeSH
• buňky MDCK MeSH
• cimetidin farmakologie   MeSH
• cyklopropany MeSH
• eliminace ledvinami MeSH
• HEK293 buňky MeSH
• inhibitory reverzní transkriptasy farmakokinetika   farmakologie   moč   MeSH
• krysa rodu Rattus MeSH
• lamivudin farmakokinetika   farmakologie   moč   MeSH
• ledviny metabolismus   MeSH
• lidé MeSH
• metformin metabolismus   farmakologie   MeSH
• plocha pod křivkou MeSH
• poločas MeSH
• potkani Wistar MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny přenášející organické kationty antagonisté a inhibitory   metabolismus   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům antagonisté a inhibitory   metabolismus   MeSH
• psi MeSH
• ROC křivka MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABCC2 protein, human MeSH Prohlížeč
• alkyny MeSH
• benzoxaziny MeSH
• cimetidin MeSH
• cyklopropany MeSH
• efavirenz MeSH Prohlížeč
• inhibitory reverzní transkriptasy MeSH
• lamivudin MeSH
• metformin MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny přenášející organické kationty MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH

OBJECTIVES: The aim of this study was to analyse the emergence of carbapenem resistance among hospital strains of Acinetobacter in the Czech Republic. METHODS: Acinetobacter isolates were collected prospectively in 2005-06 from 19 diagnostic laboratories. They were identified to species level by AFLP, typed using AFLP, pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing, and tested for susceptibility to 14 antimicrobials and for the presence of 20 genes associated with antimicrobial resistance. RESULTS: A total of 150 Acinetobacter isolates were obtained from 56 intensive care units of 20 hospitals in 15 cities. They were identified as Acinetobacter baumannii (n = 108) or other species. A. baumannii isolates were allocated to EU clone I (n = 5), EU clone II (n = 66) or other, mostly unique genotypes. Two-thirds of the clone II isolates had nearly identical AFLP and PFGE fingerprints. As many as 85% and 88% isolates were susceptible to meropenem and imipenem (or=8 mg/L were found in 23 A. baumannii isolates, of which 20 belonged to clone II. Isolates with bla(OXA-58-like) (n = 3)(,) bla(OXA-24-like) (n = 1) or ISAba1 adjacent to bla(OXA-51-like) (n = 34) had carbapenem MICs of 2 to >16 mg/L, while those without these elements showed MICs of

• MeSH
• Acinetobacter baumannii klasifikace   účinky léků   izolace a purifikace   MeSH
• analýza polymorfismu délky amplifikovaných restrikčních fragmentů MeSH
• antibakteriální látky farmakologie   MeSH
• bakteriální proteiny genetika   MeSH
• beta-laktamasy genetika   MeSH
• DNA bakterií genetika   MeSH
• DNA fingerprinting MeSH
• genotyp MeSH
• infekce bakteriemi rodu Acinetobacter epidemiologie   mikrobiologie   MeSH
• infekce spojené se zdravotní péčí epidemiologie   mikrobiologie   MeSH
• jednotky intenzivní péče MeSH
• karbapenemy farmakologie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• mnohočetná bakteriální léková rezistence * MeSH
• nemocnice MeSH
• prospektivní studie MeSH
• pulzní gelová elektroforéza MeSH
• sekvenční analýza DNA MeSH
• shluková analýza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• antibakteriální látky MeSH
• bakteriální proteiny MeSH
• beta-laktamasy MeSH
• DNA bakterií MeSH
• karbapenemy MeSH

The ATP-binding cassette family transporter MRP2 (multidrug resistance-associated protein 2), encoded by the ABCC2 gene, is involved in the renal excretion of numerous xenobiotics and it is likely that it also transports many endogenous molecules arising from not only normal essential metabolic processes but also from environmental toxins or food intake. We used a targeted gas chromatography-mass spectrometry metabolomics analysis to study whether endogenous organic anions are differentially excreted in urines of healthy volunteers according to their genotype for three functional single nucleotide polymorphisms (SNPs) in ABCC2. This was the case for 35 of the 108 metabolites analyzed. Eight of them are most likely substrates of MRP2 since they are the most contributive to the difference between carriers of a decreasing function allele vs those carrying an increasing function one. Seven out of 8 metabolites are fatty acids (dodecanoic acid; 3-hydroxypropanoic acid) or metabolites of polyphenols (caffeine; resorcinol; caffeic acid; 2-(3,4-dihydroxyphenyl) acetic acid; and 4-hydroxyhippuric acid). Most of them were structurally similar to a series of substances previously shown to interact with MRP2 function in vitro. Interestingly, coproporphyrin isomer I, a prototypical substrate of MRP2, also belonged to our final list although it was not significantly discriminant on its own. This suggests that the simultaneous measurement of a set of endogenous metabolites in urine, rather than that of unique metabolites, has the potential to provide a phenotypic measure of MRP2 function in vivo. This would represent an innovative tool to study the variability of the transport activity of MRP2 under a physiological or pathological condition, especially in pharmacokinetic studies of its substrates.

• Klíčová slova
• ABCC2, Endogenous substrates, Metabolomics, Multidrug resistance-associated protein 2, Single nucleotide polymorphisms,
• MeSH
• alely MeSH
• analýza hlavních komponent MeSH
• biologické markery moč   MeSH
• biologické modely * MeSH
• diskriminační analýza MeSH
• dospělí MeSH
• eliminace ledvinami * MeSH
• exony MeSH
• frekvence genu MeSH
• genetické asociační studie MeSH
• jednonukleotidový polymorfismus * MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolomika metody   MeSH
• mladý dospělý MeSH
• organické látky moč   MeSH
• plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• validační studie MeSH
• Geografické názvy
• Francie MeSH
• Názvy látek
• ABCC2 protein, human MeSH Prohlížeč
• biologické markery MeSH
• organické látky MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH