|
|
Pathophysiological and genetic factors affecting serum uric acid level.
Hasíková, Lenka ; Závada, Jakub (advisor) ; Hrnčíř, Zbyněk (referee) ; Horák, Pavel (referee)
Introduction: Serum uric acid level (SUA) depends on the balance between its production and excretion. SUA is associated with several transmembrane proteins responsible for reabsorption (mainly URAT1 and GLUT9) and secretion (ABCG2) on the apical and basolateral membranes of the proximal tubules in the kidney, and in the case of ABCG2, it also correlates with its significant excretion through the gastrointestinal tract. Gout is a metabolic disease caused by the deposition of urate crystals in the joints and tissues. Chronic hyperuricemia is a primary risk factor for the development of gout; however, gout patients usually have a lower SUA during an acute gout attack than in the intercritical periods. The exact mechanism of this phenomenon is unknown. It has been speculated that the systemic inflammatory response can explain this discrepancy. The aim of the study is to determine whether treatment with specific inhibitors of the proinflammatory cytokine TNF (TNFi) affects SUA in patients with systemic rheumatic disease (SRD), and whether changes in SUA correlate with changes in selected proinflammatory cytokines or with the biomarker of oxidative stress, allantoin. Another aim is to determine the frequency and effect of allelic variants in the ABCG2 urate transporter gene in patients with primary...
|
|
|
Study of effects of antiretroviral drugs on transmembrane transport of tenofofovir disoproxil fumarate across MDCKII-ABCB1 cell monolayer
Repeľová, Beáta ; Červený, Lukáš (advisor) ; Čečková, Martina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Beáta Repeľová Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Study of effects of antiretroviral drugs on transmembrane transport of tenofovir disoproxil fumarate across MDCKII - ABCB1 cell monolayer Tenofovir disoproxil fumarate (TDF) - ester prodrug of tenofovir is considered as one of the most frequently used component of combination antiretroviral therapy. Several ways of application and good patients' tolerability is typical for this compound. TDF is a substrate of dug transporter such as P-glycoprotein (P-gp) therefore its efflux activity may limit the bioavailability after oral administration and distribution of TDF. As many of antiretroviral drugs are also substrates or inhibitors of P-gp, drug - drug interactions with TDF at the level of transmembrane transport could be expected. The aim of the diploma thesis was to describe effects of co-administered antiretroviral drugs on transfer of TDF across MDCKII cell monolayer by using bidirectional transport and concentration equilibrium setups. The results of experiments confirmed that TDF is a substrate of P-gp. High values of efflux ratio describing transmembrane transport of TDF across parental cells have been observed. This...
|
|
|
Pathophysiology of urate transporters in primary gout
Pavelcová, Kateřina ; Stibůrková, Blanka (advisor) ; Doležel, Zdeněk (referee) ; Hrnčíř, Zbyněk (referee)
There are localised proteins (so-called urate transporters) in the renal proximal tubules and in the intestine, which excrete and reabsorb uric acid. Polymorphisms in the genes coding these proteins can result in the disruption of the transport function and development of hyperuricemia and gout. However the serum level of uric acid is also determined by other factors which include the intake of exogenous purines in food, synthesis of endogenous purines and degradation of nucleic acids, but also certain conditions. In 250 patients with primary hyperuricemia and gout we used Sanger sequencing to analyse the exons and adjacent intron regions in ten genes coding urate transporters: ABCG2, ABCC4, SLC2A9, SLC22A12, SLC22A11, SLC22A13, SLC17A1, SLC17A3, SLC22A6 and SLC22A8. We examined a possible connection between the identified genetic variants and primary hyperuricemia and gout based on a comparison of allele frequencies with the European population, according to topological models, according to programs predicting the functional impacts of variants and searches in specialised literature. We also took into account the conclusions of functional studies analysing the impact of nonsynonymous variants in the ABCG2 and SLC2A9 genes. We also focused on the effect of the concomitant occurrence of several...
|
|
|
Effect of ABCG2 allelic variants on the transport of uric acid
Vávra, Jiří ; Krylov, Vladimír (advisor) ; Ježek, Petr (referee)
Uric acid is a main metabolite of purine degradation in humans and in higher primates. Its increased plasmatic level is called hyperuricemia and may be the cause of gout and many other similar diseases. Uricemia is controlled by many transporters, which are located in proximal tubule of human kidney. When some transporter have abnormal function, the physiological plasmatic level of uric acid may be impaired. In genome wide association study (GWAS) it was discovered that some hyperuricemia or gout patients have ABCG2 protein damaged. This protein carries out uric acid from epithelial cell to the urine. The goal of this diploma thesis is the determination of transport capacity of ABCG2 allelic variants found via GWAS (Institute of Rheumatology of 1st medical faculty UK in Prague) in vitro with Xenopus laevis oocyte expression system. Uric acid secretion was compared with wild type variant. Keywords: Uric acid, GWAS study, Xenopus laevis, membrane transport protein, ABCG2
|
|
|
Study of effects of antiretroviral drugs on transmembrane transport of tenofofovir disoproxil fumarate across MDCKII-ABCB1 cell monolayer
Repeľová, Beáta ; Červený, Lukáš (advisor) ; Čečková, Martina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Beáta Repeľová Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Study of effects of antiretroviral drugs on transmembrane transport of tenofovir disoproxil fumarate across MDCKII - ABCB1 cell monolayer Tenofovir disoproxil fumarate (TDF) - ester prodrug of tenofovir is considered as one of the most frequently used component of combination antiretroviral therapy. Several ways of application and good patients' tolerability is typical for this compound. TDF is a substrate of dug transporter such as P-glycoprotein (P-gp) therefore its efflux activity may limit the bioavailability after oral administration and distribution of TDF. As many of antiretroviral drugs are also substrates or inhibitors of P-gp, drug - drug interactions with TDF at the level of transmembrane transport could be expected. The aim of the diploma thesis was to describe effects of co-administered antiretroviral drugs on transfer of TDF across MDCKII cell monolayer by using bidirectional transport and concentration equilibrium setups. The results of experiments confirmed that TDF is a substrate of P-gp. High values of efflux ratio describing transmembrane transport of TDF across parental cells have been observed. This...
|
|
|
Study of effects of antiretroviral drugs on transmembrane transport of tenofofovir disoproxil fumarate across MDCKII-ABCB1 cell monolayer
Repeľová, Beáta ; Červený, Lukáš (advisor) ; Čečková, Martina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Beáta Repeľová Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Study of effects of antiretroviral drugs on transmembrane transport of tenofovir disoproxil fumarate across MDCKII - ABCB1 cell monolayer Tenofovir disoproxil fumarate (TDF) - ester prodrug of tenofovir is considered as one of the most frequently used component of combination antiretroviral therapy. Several ways of application and good patients' tolerability is typical for this compound. TDF is a substrate of dug transporter such as P-glycoprotein (P-gp) therefore its efflux activity may limit the bioavailability after oral administration and distribution of TDF. As many of antiretroviral drugs are also substrates or inhibitors of P-gp, drug - drug interactions with TDF at the level of transmembrane transport could be expected. The aim of the diploma thesis was to describe effects of co-administered antiretroviral drugs on transfer of TDF across MDCKII cell monolayer by using bidirectional transport and concentration equilibrium setups. The results of experiments confirmed that TDF is a substrate of P-gp. High values of efflux ratio describing transmembrane transport of TDF across parental cells have been observed. This...
|
|
|
The structure and function of transmembrane proteins ABCG2
Vávra, Jiří ; Mančíková, Andrea (advisor) ; Novotný, Marian (referee)
ABCG2 (ABCP/MXR/BCRP) transporters create homodimers through the plasma membrane. They play an important role in transmembrane transport of a wide spectrum of biological substrates. They are essential for renal, intestinal, placental and haematoencephalic barrier function. In particular they perform an excretory function, protect cells against toxic compounds and xenobiotic cumulation. They are also involved in metabolic regulation of stem cells. This bachelor thesis summarizes information about ABCG2 protein function, their physiological role in humans and other mammals. Keywords: ABCG2, BCRP, membrane transporters, multidrug resistention (MDR), ATP binding cassette family (ABC)
|
guest ::
