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Metabolism of estrogene in UGT1A1-deficient rats
Módos, Anna ; Muchová, Lucie (advisor) ; Brůha, Radan (referee)
Introduction Estrogen-induced cholestasis is a disease characterized by a failure of bile flow and bile production. It can develop in women after oral contraceptives use, hormone replacement therapy or during pregnancy. The estrogen metabolism is a complex process leading to formation of metabolites with different biological activities. It takes place primarily in the liver (Phase I and Phase II including hydroxylation, methylation, sulfation and glucuronidation). The enzymes from UDP-glucuronosyltransferases family , abbreviated UGT, are responsible for the glucuronidation of estrogens. Aims The objective of my work is to define estrogen metabolism and gene expression of UGT1A1, CYP1A2 and SULT1A1 and characterize cholestatic liver damage in the UGT1A1 deficient rat strain (Gunn rats) compared to rats with normal enzyme activity and try to define possible mechanisms responsible for the liver damage. Methods Adult female Gunn and corresponding heterozygous rats were treated with ethinylestradiol (EE, 5 mg/kg body weight SC) for 5 days, while control rats received propanediol (vehicle). Day six, the animals were sacrificed and plasma and liver tissue were collected for analysis. Markers of cholestasis and liver damage ALP, AST, ALT and bilirubin were determined using an automatic analyzer, total...
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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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Induction of heme oxygenase and biological role of its metabolic products.
Šuk, Jakub ; Muchová, Lucie (advisor) ; Jirsa, Milan (referee) ; Neužil, Jiří (referee)
Heme oxygenase (HMOX) catalyzes first and rate-limiting step in heme degradation. By its action, carbon monoxide (CO), ferrous iron and biliverdin which is subsequently reduced to bilirubin are produced. Before discovery of HMOX reaction mechanism, CO was considered only a toxic waste product without any significant importance for human organism. Bilirubin, marker of liver dysfunction, has been also exposed to similar perception. But results from past decades show that HMOX and its metabolic products play an important role in number of physiological as well as defense against pathophysiological processes. The aim of this thesis was to clarify the role of HMOX and its metabolic products, presumably CO and bilirubin, in vivo and in vitro. We focused on the role of CO in a rat model of lipopolysaccharide-induced cholestasis. We were first to describe tissue distribution and pharmacokinetics of inhaled CO in this animal model and found out that CO inhalation is associated with anti-inflammatory and hepatoprotective effects. In a rat model of ethinylestradiol-induced cholestasis, we demonstrated the anticholestatic effect of HMOX. The induction of HMOX by its substrate heme increased the expression of liver transporters thereby increasing bile flow and simultaneously facilitated effective clearance of...
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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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Metabolism of estrogene in UGT1A1-deficient rats
Módos, Anna ; Muchová, Lucie (advisor) ; Brůha, Radan (referee)
Introduction Estrogen-induced cholestasis is a disease characterized by a failure of bile flow and bile production. It can develop in women after oral contraceptives use, hormone replacement therapy or during pregnancy. The estrogen metabolism is a complex process leading to formation of metabolites with different biological activities. It takes place primarily in the liver (Phase I and Phase II including hydroxylation, methylation, sulfation and glucuronidation). The enzymes from UDP-glucuronosyltransferases family , abbreviated UGT, are responsible for the glucuronidation of estrogens. Aims The objective of my work is to define estrogen metabolism and gene expression of UGT1A1, CYP1A2 and SULT1A1 and characterize cholestatic liver damage in the UGT1A1 deficient rat strain (Gunn rats) compared to rats with normal enzyme activity and try to define possible mechanisms responsible for the liver damage. Methods Adult female Gunn and corresponding heterozygous rats were treated with ethinylestradiol (EE, 5 mg/kg body weight SC) for 5 days, while control rats received propanediol (vehicle). Day six, the animals were sacrificed and plasma and liver tissue were collected for analysis. Markers of cholestasis and liver damage ALP, AST, ALT and bilirubin were determined using an automatic analyzer, total...
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