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Bilirubin secretory pathway and its disorders.
Sticová, Eva ; Jirsa, Milan (advisor) ; Bronský, Jiří (referee) ; Jirásek, Tomáš (referee)
Identification and functional characterization of numerous transport systems at the sinusoidal and canalicular membrane of hepatocytes have significantly expanded our understanding of bilirubin metabolism and contributed to elucidation of molecular basis of hereditary jaundice. Moreover, dysregulation of hepatobiliary transport systems could explain jaundice in many acquired liver disorders. This thesis is focused on the new aspects of bilirubin handling in hepatocytes based on elucidation of the molecular basis of Rotor syndrome. The first study is focused on the antioxidative properties of bilirubin in liver tissue in a model of obstructive cholestasis. In the second part of the thesis we present several novel mutations in ABCC2, the gene associated with Dubin-Johnson syndrome, identified in patients selected for the Rotor locus mapping study. In the key third study concerned with Rotor syndrome we demonstrated that biallelic inactivating mutations causing complete absence of transport proteins OATP1B1 and OATP1B3 result in disruption of hepatic reuptake of bilirubin, which is the molecular basis of Rotor-type jaundice. These results indicate that apart from secretion of conjugated bilirubin into bile, a significant fraction of bilirubin glucuronide is secreted via MRP3 into sinusoidal blood and...
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Bilirubin influence on the progression of inflammatory bowel disease.
Patková, Anna ; Nachtigal, Petr (advisor) ; Hronek, Miloslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Bilirubin influence on the progression of inflammatory bowel disease Diploma thesis Anna Patková Supervisor: doc. PharmDr. Petr Nachtigal, Ph.D. Background: Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gut caused by an interaction of genetic and environmental factors. It is thought that tissue damage is also partly caused by an oxidative stress. Heme oxygenase-1 and bilirubin are strong antioxidants and both of them provide an anti-inflammatory effect in various tissues. The aim of this diploma thesis was to detect changes of expression of HO-I in the large intestine of normobilirubinemic and hyperbilirubinemic rats after the induction of acute or chronic experimental colitis. Methods: We used Gunn rats with hereditary defect of UDP-glucuronyltransferase, which causes hyperbilirubinemia. The control group of animals was made up of heterozygous littermates of the Gunn rats, which have normal serum bilirubin levels. All animals were treated by dextran sulfate sodium in order to induce an experimental colitis. Rats were divided into two groups. Each of them contained hyperbilirubinemic and normobilirubinemic...
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Inherited Disorders of Bilirubin Metabolism
Šlachtová, Lenka ; Martásek, Pavel (advisor) ; Baxová, Alice (referee)
Inherited disorders of bilirubin metabolism - hereditary hyperbilirubinemias - are metabolic disorders manifested in early childhood. Unconjugated hyperbilirubinemias result from the defect of the enzyme uridine diphosphoglucuronosyltransferase (UGT1A1). UGT1A1 mediates the conjugation of bilirubin with glucuronid acid in hepatocytes and its elimination to water soluble compound. In the next step of bilirubin degradation the transport of conjugated bilirubin from hepatocyte into the bile occure. It is caused by the ATP dependent transporters ABCC2, ATP1B1 and OATP1B3. Mutations in the genes coding the bilirubin transporters results in conjugated hyperbilirubinemia Dubin-Johnson or Rotor syndrome. This study is focused on unconjugated hyperbilirubinemia in adolescents including the non-typical manifestations and the defects of ABCC2 transporter and their phenotype in humans.
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Determination of bilirubine oxidation products
Čepa, Adam ; Smrček, Stanislav (advisor) ; Muchová, Lucie (referee)
This thesis is focused on protective and antioxidant properties of bile pigment bilirubin. Bilirubin is a potent scavenger of free radicals and reactive oxygen species generated by increased oxidative stress. Mildly elevated systemic levels of bilirubin are actually associated with lower incidence of oxidative stress-mediated diseases, such as cardiovascular disease, atherosclerosis, diabetes and certain types of cancer. The main aim of this thesis was to prepare bilirubin oxidation products in vitro, characterize their physical-chemical properties and thein determine biological impact.
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Preparation of radiolabelled bilirubin
Čepa, Adam ; Smrček, Stanislav (advisor) ; Moša, Marek (referee)
This thesis is dedicated to reasearch in radiolabeling bile pigment bilirubin. Minority bilirubin present in the body the form unconjugated. In this work, it was crucial synthesize radiolabeled bilirubin which could be monitored by detector in vitro experiments. A possible further applications, such bilirubin would be detectable in vivo experiments using µ-PET/SPECT (micro- positron emission tomography/single photon emission computed tomography) . The aim of this thesis propose variation for possible signs of bilirubin radioisotopes and synthesis of bilirubin derivates suitable for radioactive labeling. Another objektive of this work is the synthesis and study of the well-known derivative ranarubin called bilirubin, which could potentially have very simile characteristics, such as bilirubin and therefore would be a good candidate for radioisotope labeling and study of biological systems.
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Bilrubin - physicochemical properties and biochemical importance
Kupcová, Kristýna ; Hudeček, Jiří (advisor) ; Martínková, Markéta (referee)
This thesis briefly summarizes the literary data concerning bilirubin. In addititon to this, its experimental part is devoted to comparison of stability of bilirubin and its derivative, ranarubin, towards photolysis in aerobic conditions. The photolytic experiments were carried out at wavelength 366 nm for 4 hours. The resulting photolysates were characterised by absorption spectroscopy (400 - 800 nm) and mass spectrometry. The data obtained show a high degree of similarity for both compounds, which are both relatively stable against photolytic splitting and photooxidation to biliverdin.
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Study of thiol addition to biliverdine, the synthesis of labelled bilirubine
Felklová, Veronika ; Lešetický, Ladislav (advisor) ; Smrček, Stanislav (referee)
Biliverdin and bilirubin are bile pigments which are degradation products of heme. Biliverdin (BV) is greenish-blue pigment and is reduction product of tetrapyrrolic core of heme by influence of the hemoxygenase (HO). The final product of this degradation is yellowish-brown pigment bilirubin (BR) which forms from BV thanks to the biliverdinreduktase (BVR). Normal and slightly raised level of bilirubin in plasma has cytoprotective effects whereas high levels are cytotoxic often. In severe unconjugated hyperbilirubinemia cases (newborn children) unconjugated bilirubin (UCB) accumulates in central nervous system (CNS) and causes bilirubin-induced neurologic dysfunction (BIND). Unfortunately there is a limitation for finding UCB pathophysiology caused by difficult determination of UCB content and distribution in tissues and biological fluids. So the main purpose of this thesis is to find and integrate isolated methods which will serve as the basis of finding bilirubin distribution. This progress would have a significant effect on studies of bilirubin neurotoxicity on newborn children. This method is based on radioactive labeling of UCB. Preferentially atom C 10 used for binding suitable functional group (thiols) because conformation of indicated bilirubin shouldn't change in this position. And then the...
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Development of new method for the determination of bilirubin and its esters
KAMIŠOVÁ, Tereza
This work describes present knowledge of bilirubin, its metabolism in human body and attributes necessary to its determination by high performance liquid chromatography (HPLC). Its similarity with phycobilins is summarized. Bilirubin nonpolar esters could be used to prepare self-assembling light-harvesting antennas. The experimental part involves modification of a mobile phase for HPLC determination of bilirubin and its esters, which were synthesized by Fisher esterification.
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