The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3, CPS1, and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients' poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers.

• Klíčová slova
• ABCC3, CPS1, Stony Brook taxanes, TRIP6, multidrug resistance, ovarian carcinoma, taxanes,
• MeSH
• adaptorové proteiny signální transdukční genetika   MeSH
• chemorezistence genetika   MeSH
• down regulace účinky léků   genetika   MeSH
• epiteliální ovariální karcinom farmakoterapie   genetika   MeSH
• karbamoylfosfátsynthasa (amoniak) genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• myši nahé MeSH
• myši MeSH
• nádorové biomarkery genetika   MeSH
• nádorové buněčné linie MeSH
• nádory vaječníků farmakoterapie   genetika   MeSH
• paclitaxel terapeutické užití   MeSH
• proteiny s doménou LIM genetika   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   MeSH
• taxoidy terapeutické užití   MeSH
• transkripční faktory genetika   MeSH
• viabilita buněk účinky léků   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• CPS1 protein, human MeSH Prohlížeč
• karbamoylfosfátsynthasa (amoniak) MeSH
• multidrug resistance-associated protein 3 MeSH Prohlížeč
• nádorové biomarkery MeSH
• paclitaxel MeSH
• proteiny s doménou LIM MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH
• taxoidy MeSH
• transkripční faktory MeSH
• TRIP6 protein, human MeSH Prohlížeč

In natural environments, antibiotics are important means of interspecies competition. At subinhibitory concentrations, they act as cues or signals inducing antibiotic production; however, our knowledge of well-documented antibiotic-based sensing systems is limited. Here, for the soil actinobacterium Streptomyces lincolnensis, we describe a fundamentally new ribosome-mediated signaling cascade that accelerates the onset of lincomycin production in response to an external ribosome-targeting antibiotic to synchronize antibiotic production within the population. The entire cascade is encoded in the lincomycin biosynthetic gene cluster (BGC) and consists of three lincomycin resistance proteins in addition to the transcriptional regulator LmbU: a lincomycin transporter (LmrA), a 23S rRNA methyltransferase (LmrB), both of which confer high resistance, and an ATP-binding cassette family F (ABCF) ATPase, LmrC, which confers only moderate resistance but is essential for antibiotic-induced signal transduction. Specifically, antibiotic sensing occurs via ribosome-mediated attenuation, which activates LmrC production in response to lincosamide, streptogramin A, or pleuromutilin antibiotics. Then, ATPase activity of the ribosome-associated LmrC triggers the transcription of lmbU and consequently the expression of lincomycin BGC. Finally, the production of LmrC is downregulated by LmrA and LmrB, which reduces the amount of ribosome-bound antibiotic and thus fine-tunes the cascade. We propose that analogous ABCF-mediated signaling systems are relatively common because many ribosome-targeting antibiotic BGCs encode an ABCF protein accompanied by additional resistance protein(s) and transcriptional regulators. Moreover, we revealed that three of the eight coproduced ABCF proteins of S. lincolnensis are clindamycin responsive, suggesting that the ABCF-mediated antibiotic signaling may be a widely utilized tool for chemical communication. IMPORTANCE Resistance proteins are perceived as mechanisms protecting bacteria from the inhibitory effect of their produced antibiotics or antibiotics from competitors. Here, we report that antibiotic resistance proteins regulate lincomycin biosynthesis in response to subinhibitory concentrations of antibiotics. In particular, we show the dual character of the ABCF ATPase LmrC, which confers antibiotic resistance and simultaneously transduces a signal from ribosome-bound antibiotics to gene expression, where the 5' untranslated sequence upstream of its encoding gene functions as a primary antibiotic sensor. ABCF-mediated antibiotic signaling can in principle function not only in the induction of antibiotic biosynthesis but also in selective gene expression in response to any small molecules targeting the 50S ribosomal subunit, including clinically important antibiotics, to mediate intercellular antibiotic signaling and stress response induction. Moreover, the resistance-regulatory function of LmrC presented here for the first time unifies functionally inconsistent ABCF family members involving antibiotic resistance proteins and translational regulators.

• Klíčová slova
• ABCF ATPase, Streptomyces, antibiotic biosynthesis, antibiotic resistance, antibiotic-mediated signaling, chemical communication, regulation of gene expression, ribosomal regulation, signal transduction, specialized metabolism,
• MeSH
• adenosintrifosfatasy metabolismus   MeSH
• antibakteriální látky biosyntéza   farmakologie   MeSH
• bakteriální léková rezistence MeSH
• bakteriální proteiny genetika   metabolismus   MeSH
• linkomycin biosyntéza   farmakologie   MeSH
• methyltransferasy MeSH
• multigenová rodina MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   metabolismus   MeSH
• regulace genové exprese u bakterií účinky léků   MeSH
• ribozomy metabolismus   MeSH
• signální transdukce MeSH
• Streptomyces metabolismus   MeSH
• transkripční faktory MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosintrifosfatasy MeSH
• antibakteriální látky MeSH
• bakteriální proteiny MeSH
• linkomycin MeSH
• methyltransferasy MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH
• rRNA (adenosine-O-2'-)methyltransferase MeSH Prohlížeč
• transkripční faktory MeSH

Special attention is required when pharmacological treatment is indicated for a pregnant woman. P-glycoprotein (MDR1) is a well-known transporter localized in the maternal blood-facing apical membrane of placental syncytiotrophoblast and is considered to play an important role in protecting the developing fetus. Maraviroc, a MDR1 substrate that is registered for treatment of HIV infection, shows a low toxicity profile, suggesting favorable tolerability also if administered to pregnant women. Nevertheless, there is only poor understanding to date regarding the extent to which it permeates across the placental barrier and what are the transport mechanisms involved. Endeavoring to clarify the passage of maraviroc across placenta, we used in this study the method of closed-circuit perfusion of maraviroc across human placental cotyledon. The data obtained confirmed slight involvement of MDR1, but they also suggest possible interaction with other transport system(s) working in the opposite direction from that of MDR1. Complementary in vitro studies, including cellular experiments on choriocarcinoma BeWo cells as well as transporter-overexpressing MDCKII and A431 cell lines and accumulation in placental fresh villous fragments, revealed maraviroc transport by MRP1, OATP1A2, and OATP1B3 transporters. Based on mRNA expression data in the placental tissue, isolated trophoblasts, and fetal endothelial cells, especially MRP1 and OATP1A2 seem to play a crucial role in cooperatively driving maraviroc into placental tissue. By the example of maraviroc, we show here the important interplay of transporters in placental drug handling and its possibility to overcome the MDR1-mediated efflux.

• Klíčová slova
• Drug transporters, Drug–drug interactions, MRP1, Maraviroc, OATP, Placenta,
• MeSH
• akridiny farmakologie   MeSH
• buňky MDCK MeSH
• látky proti HIV krev   metabolismus   farmakologie   MeSH
• lékové interakce MeSH
• lidé MeSH
• maravirok krev   metabolismus   MeSH
• nádorové buněčné linie MeSH
• P-glykoproteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• perfuze MeSH
• placenta účinky léků   metabolismus   MeSH
• placentární oběh MeSH
• přenašeče organických aniontů antagonisté a inhibitory   genetika   metabolismus   MeSH
• protein OATP1B3 antagonisté a inhibitory   genetika   metabolismus   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   metabolismus   MeSH
• psi MeSH
• regulace genové exprese MeSH
• ritonavir farmakologie   MeSH
• těhotenství MeSH
• tetrahydroisochinoliny farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• psi MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABCB1 protein, human MeSH Prohlížeč
• akridiny MeSH
• Elacridar MeSH Prohlížeč
• látky proti HIV MeSH
• maravirok MeSH
• multidrug resistance-associated protein 1 MeSH Prohlížeč
• P-glykoproteiny MeSH
• přenašeče organických aniontů MeSH
• protein OATP1B3 MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH
• ritonavir MeSH
• SLCO1A2 protein, human MeSH Prohlížeč
• SLCO1B3 protein, human MeSH Prohlížeč
• tetrahydroisochinoliny MeSH

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, caused by various factors, such as the aggressiveness of the disease, the limited therapeutic options and the lack of early detection and risk markers. The ATP binding cassette subfamily C member 2 (ABCC2) protein plays a critical role in response to various drugs and is differentially expressed in gemcitabine sensitive and resistant cells. Moreover, single nucleotide polymorphisms (SNPs) in the gene have been associated with differential outcomes and prognosis in several tumour types. The aim of this study was to investigate the possible association between SNPs in the ABCC2 gene and overall survival (OS) in PDAC patients. We analysed 12 polymorphisms, including tagging-SNPs covering all the genetic variability of the ABCC2 gene and genotyped them in 1415 PDAC patients collected within the Pancreatic Disease ReseArch (PANDoRA) consortium. We tested the association between ABCC2 SNPs and PDAC OS using Cox proportional hazard models. We analysed PDAC patients dividing them by stage and observed that the minor alleles of three SNPs showed an association with worse OS [rs3740067: hazard ratio (HR) = 3.29, 95% confidence interval (CI) = 1.56-6.97, P = 0.002; rs3740073: HR = 3.11, 95% CI = 1.52-6.38, P = 0.002 and rs717620: HR = 2.90, 95% CI = 1.41-5.95, P = 0.004, respectively] in stage I patients. In patients with more advanced PDAC, we did not observe any statistically significant association. Our results suggest that rs3740067, rs3740073 and rs717620 could be promising prognostic markers in stage I PDAC patients.

• MeSH
• duktální karcinom slinivky břišní genetika   mortalita   patologie   terapie   MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus * MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• nádorové biomarkery genetika   MeSH
• nádory slinivky břišní genetika   mortalita   patologie   terapie   MeSH
• následné studie MeSH
• prognóza MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   MeSH
• regulace genové exprese u nádorů MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABCC2 protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům 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

Genome structure characterization can contribute to a better understanding of processes such as adaptation, speciation, and karyotype evolution, and can provide useful information for refining genome assemblies. We studied the genome of an important North American boreal forest pest, the spruce budworm, Choristoneura fumiferana, through a combination of molecular cytogenetic analyses and construction of a high-density linkage map based on single nucleotide polymorphism (SNP) markers obtained through a genotyping-by-sequencing (GBS) approach. Cytogenetic analyses using fluorescence in situ hybridization methods confirmed the haploid chromosome number of n = 30 in both sexes of C. fumiferana and showed, for the first time, that this species has a WZ/ZZ sex chromosome system. Synteny analysis based on a comparison of the Bombyx mori genome and the C. fumiferana linkage map revealed the presence of a neo-Z chromosome in the latter species, as previously reported for other tortricid moths. In this neo-Z chromosome, we detected an ABC transporter C2 (ABCC2) gene that has been associated with insecticide resistance. Sex-linkage of the ABCC2 gene provides a genomic context favorable to selection and rapid spread of resistance against Bacillus thuringiensis serotype kurstaki (Btk), the main insecticide used in Canada to control spruce budworm populations. Ultimately, the linkage map we developed, which comprises 3586 SNP markers distributed over 30 linkage groups for a total length of 1720.41 cM, will be a valuable tool for refining our draft assembly of the spruce budworm genome.

• Klíčová slova
• Choristoneura fumiferana, genotyping-by-sequencing, karyotype, linkage map, neo-Z chromosome,
• MeSH
• chromozomy hmyzu genetika   MeSH
• genetická vazba * MeSH
• genom hmyzu * MeSH
• hmyzí proteiny genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• Lepidoptera genetika   MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   MeSH
• rezistence k insekticidům MeSH
• syntenie MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• hmyzí proteiny MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům 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

Moderate neonatal jaundice is the most common clinical condition during newborn life. However, a combination of factors may result in acute hyperbilirubinemia, placing infants at risk of developing bilirubin encephalopathy and death by kernicterus. While most risk factors are known, the mechanisms acting to reduce susceptibility to bilirubin neurotoxicity remain unclear. The presence of modifier genes modulating the risk of developing bilirubin-induced brain damage is increasingly being recognised. The Abcb1 and Abcc1 members of the ABC family of transporters have been suggested to have an active role in exporting unconjugated bilirubin from the central nervous system into plasma. However, their role in reducing the risk of developing neurological damage and death during neonatal development is still unknown.To this end, we mated Abcb1a/b-/- and Abcc1-/- strains with Ugt1-/- mice, which develop severe neonatal hyperbilirubinemia. While about 60% of Ugt1-/- mice survived after temporary phototherapy, all Abcb1a/b-/-/Ugt1-/- mice died before postnatal day 21, showing higher cerebellar levels of unconjugated bilirubin. Interestingly, Abcc1 role appeared to be less important.In the cerebellum of Ugt1-/- mice, hyperbilirubinemia induced the expression of Car and Pxr nuclear receptors, known regulators of genes involved in the genotoxic response.We demonstrated a critical role of Abcb1 in protecting the cerebellum from bilirubin toxicity during neonatal development, the most clinically relevant phase for human babies, providing further understanding of the mechanisms regulating bilirubin neurotoxicity in vivo. Pharmacological treatments aimed to increase Abcb1 and Abcc1 expression, could represent a therapeutic option to reduce the risk of bilirubin neurotoxicity.

• MeSH
• bilirubin toxicita   MeSH
• glukuronosyltransferasa fyziologie   MeSH
• lidé MeSH
• modely nemocí na zvířatech * MeSH
• mozeček účinky léků   patologie   MeSH
• myši knockoutované MeSH
• myši MeSH
• neurotoxické syndromy etiologie   metabolismus   patologie   MeSH
• novorozená zvířata MeSH
• novorozenecká hyperbilirubinemie komplikace   metabolismus   patologie   MeSH
• P-glykoprotein genetika   metabolismus   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   metabolismus   MeSH
• viabilita buněk MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• bilirubin MeSH
• glukuronosyltransferasa MeSH
• multidrug resistance-associated protein 1 MeSH Prohlížeč
• P-glykoprotein MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH
• UGT1A1 enzyme MeSH Prohlížeč

Ganciclovir (GCV) is the cornerstone of cytomegalovirus prevention and treatment in transplant patients. It is associated with problematic adverse hematological effects in this population of immunosuppressed patients, which may lead to dose reduction thus favoring resistance. GCV crosses the membranes of cells, is activated by phosphorylation, and then stops the replication of viral DNA. Its intracellular accumulation might favor host DNA polymerase inhibition, hence toxicity. Following this hypothesis, we investigated the association between a selected panel of membrane transporter polymorphisms and the evolution of neutrophil counts in n=174 renal transplant recipients. An independent population of n=96 renal transplants served as a replication and experiments using HEK293T-transfected cells were performed to validate the clinical findings. In both cohorts, we found a variant in ABCC4 (rs11568658) associated with decreased neutrophil counts following valganciclovir (GCV prodrug) administration (exploratory cohort: β±SD=-0.68±0.28, p=0.029; replication cohort: β±SD=-0.84±0.29, p=0.0078). MRP4-expressing cells showed decreased GCV accumulation as compared to negative control cells (transfected with an empty vector) (-61%; p<0.0001). The efflux process was almost abolished in cells expressing MRP4 rs11568658 variant protein. Molecular dynamic simulations of GCV membrane crossing showed a preferred location of the drug just beneath the polar head group region, which supports its interaction with efflux transporters.

• Klíčová slova
• Cytomegalovirus, Ganciclovir, Membrane transporters, Multidrug resistance-associated protein 4, Pharmacogenetics, Transplantation,
• MeSH
• antivirové látky * škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• cytomegalovirové infekce prevence a kontrola   MeSH
• dospělí MeSH
• ganciklovir * škodlivé účinky   farmakokinetika   MeSH
• HEK293 buňky MeSH
• jednonukleotidový polymorfismus MeSH
• Jurkat buňky MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• neutropenie chemicky indukované   genetika   metabolismus   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transplantace ledvin MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• ABCC4 protein, human MeSH Prohlížeč
• antivirové látky * MeSH
• ganciklovir * MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH

Dual hereditary jaundice, a combination of Dubin-Johnson and Gilbert's syndromes, is a rare clinical entity resulting from the compound defects of bilirubin conjugation and transport. We aimed to study the hereditary jaundice in 56 members from seven seemingly unrelated Roma families, to find the causal genetic defect and to estimate its origin in Roma population. On the basis of biochemical results of total and conjugated serum bilirubin and clinical observations, ABCC2 gene, TATA box and phenobarbital enhancer (PBREM) of UGT1A1 gene were analyzed by sequencing, RFLP and fragment analysis. We found a novel variant c.1013_1014delTG in the eighth exon of ABCC2 gene in 17 individuals in homozygous state. Dual defect NG_011798.1:c.[1013_1014delTG]; NG_002601.2:g.[175492_175493insTA] in homozygous state was found in four subjects. Biochemical analyses of porphyrins and coproporphyrin isomers in urine performed by HPLC showed inverted ratio of excreted coproporphyrin, with the predominance of coproporphyrin I (up to 100%), typical for patients with Dubin-Johnson syndrome. Pursuant cultural and social specifics of the population led us to suspect a founder effect; therefore, we performed a haplotype study using genotyping data from Affymetrix Genome-Wide Human SNP Array 6.0. As a result, we detected a common 86 kbp haplotype encompassing promoter and part of the ABCC2 coding region among all families, and estimated the age of the ancestral variant to 178-185 years. In this study, we found a novel deletion in ABCC2 gene, described genetic and biochemical features of dual hereditary jaundice and confirmed the existence of founder effect and common haplotype among seven Roma families.

• MeSH
• bilirubin metabolismus   MeSH
• delece genu * MeSH
• efekt zakladatele * MeSH
• Gilbertova nemoc diagnóza   genetika   MeSH
• glukuronosyltransferasa genetika   MeSH
• haplotypy MeSH
• homozygot MeSH
• jednonukleotidový polymorfismus MeSH
• koproporfyriny moč   MeSH
• lidé MeSH
• polymorfismus délky restrikčních fragmentů MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   MeSH
• TATA box MeSH
• žloutenka chronická idiopatická diagnóza   genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABCC2 protein, human MeSH Prohlížeč
• bilirubin MeSH
• glukuronosyltransferasa MeSH
• koproporfyriny MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH
• UGT1A1 enzyme MeSH Prohlížeč