Inherited hyperbilirubinemias are a group of metabolic disorders, characterized by increased levels of total serum bilirubin or its conjugated fraction. Most of these hyperbilirubinemias are inherited autosomal recessively and are manifested in young age. Increased bilirubin reflects the genetic disturbances in one of the enzymes of heme degradation pathway, the defect of bilirubin conjugation (UGT1A1 gene) or its transport (ABCC2, OATP1B1, OATP1B3). All of these proteins are involved not only in elimination of bilirubin, but various substrates; therefore the performed studies have a great pharmacogenomics impact. We have studied the molecular pathology of hereditary hyperbilirubinemias in Caucasian and Roma population and to compare the clinical and biochemical results with the molecular genetic data. We described the impact of compound defect of c.-3279T>G and g.175492_175493insTA on total serum bilirubin and calculated the linkage disequlibrium of these two variants in promoter region of UGT1A1 gene. We also verified, that the population distribution of both variants is in concordance with the literature. In our second study, we have described the rare conjugated hyperbilirubinemia Dubin-Johnson type among 7 Roma families. We have found a novel variant NG_011798.1:c.[1013_1014delTG] together with...

Present work has been focused on the importance of the products of the heme catabolic pathway, in particular under conditions of unconjugated hyperbilirubinemias (neonatal jaundice and Crigler-Najjar syndrome (CNS)). The second part of the project was focused on the improvement of some pharmacological approaches used in the treatment of these diseases, as well as on studies of bilirubin products that are formed during the treatment by phototherapy (PT). Neonatal jaundice is one of the most common complications in neonates. Currently, there is no efficient pharmacotherapy and the treatment with blue light is used as a gold standard for severe neonatal jaundice. However, the absolute safety of PT has still not been confirmed. In this context, it is important to note that some neonatologists start the PT before serum bilirubin levels reach the recommended values and that patients with CNS type I (CNSI) are forced to be on life-long PT (unless undergoing liver transplantation). The focus of the present project was to study biological effects of bilirubin photoisomers (PI) in an in vitro model of the human neuroblastoma SH-SY5Y cells that are used for studies of the neuronal metabolism. In further studies performed on animal model of hyperbilirubinemic rats and mice, we investigated a suitable gene...

Present work has been focused on the importance of the products of the heme catabolic pathway, in particular under conditions of unconjugated hyperbilirubinemias (neonatal jaundice and Crigler-Najjar syndrome (CNS)). The second part of the project was focused on the improvement of some pharmacological approaches used in the treatment of these diseases, as well as on studies of bilirubin products that are formed during the treatment by phototherapy (PT). Neonatal jaundice is one of the most common complications in neonates. Currently, there is no efficient pharmacotherapy and the treatment with blue light is used as a gold standard for severe neonatal jaundice. However, the absolute safety of PT has still not been confirmed. In this context, it is important to note that some neonatologists start the PT before serum bilirubin levels reach the recommended values and that patients with CNS type I (CNSI) are forced to be on life-long PT (unless undergoing liver transplantation). The focus of the present project was to study biological effects of bilirubin photoisomers (PI) in an in vitro model of the human neuroblastoma SH-SY5Y cells that are used for studies of the neuronal metabolism. In further studies performed on animal model of hyperbilirubinemic rats and mice, we investigated a suitable gene...

In newborns, unconjugated bilirubin (UCB) is not readily excreted, and when bilirubin levels exceed the serum albumin binding capacity, pathological levels of UCB exist. Hyperbilirubinemia may lead to auditory damage and ultimately cause a hearing disorder called auditory neuropathy/dys-synchrony, characterized by absent or abnormal brainstem auditory evoked potentials (BAEPs) with evidence of normal inner ear function assessed by either otoacoustic emissions or cochlear microphonic responses. Phototherapy and double volume exchange transfusion are used as treatment methods for neonatal hyperbilirubinemia. Spontaneously jaundiced Gunn rat pups given sulfadimethoxine to displace bilirubin from serum albumin develop bilirubin encephalopathy and have abnormal BAEPs comparable to human neonates. BAEPs are a noninvasive electrophysiological measure of neural function of the auditory system. High levels of calcineurin activity are believed to be involved in the mechanism of this bilirubin induced auditory neuropathy. FK506, a calcineurin inhibitor, was administered 3 hours prior to sulfa in concentrations of 0.1mg/kg, 1.0mg/kg, and 10.0mg/kg body weight. Due to the observation that all animals had abnormal BAEPs after treatment with FK506 and sulfa, it can be concluded that none of the treatment doses protected against bilirubin induced auditory impairment.

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...

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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Thesis (M.Sc. (Biochemistry)--Mahidol University, 1983.

Thesis (Ph.D.) - University of Queensland, 2006. / Includes bibliographical references.