Hepatic uptake of organic anions affects the plasma bilirubin level in subjects with Gilbert's syndrome mutations in UGT1A1

Autor: Igino Rigato, Claudio Tiribelli, Eliana Persico, P.J. Bosma, Marcello Persico, Antonio Amoroso, Roberto Torella, J.D. Ostrow, C.T.M. Bakker
Přispěvatelé: Persico, M, Persico, E, Bakker, Ctm, Rigato, I, Amoroso, A, Torella, R, Bosman, Pj, Tiribelli, Claudio, Ostrow, Jd, Other departments
Rok vydání: 2001
Předmět:
Adult
Male
medicine.medical_specialty
Glucuronosyltransferase
Bilirubin
Glucuronidation
blood/metabolism
Hemolysis
blood/genetics/metabolism
Sulfobromophthalein
chemistry.chemical_compound
blood
Reference Values
Internal medicine
medicine
Humans
Gilbert Disease
genetics
Hyperbilirubinemia
Unconjugated hyperbilirubinemia
Hepatology
biology
beta-Thalassemia
Middle Aged
medicine.disease
Gilbert's syndrome
Endocrinology
Liver
chemistry
Adult
Bilirubin
blood
Female
Gilbert Disease
blood/genetics/metabolism
Glucuronosyltransferase
genetics
Hemolysis
Humans
Hyperbilirubinemia
blood/metabolism
Indicators and Reagents
pharmacokinetics
Liver
metabolism
Male
Middle Aged
Mutation
physiology
Reference Values
Sulfobromophthalein
pharmacokinetics
beta-Thalassemia
physiology
Mutation
Bilirubin transport
biology.protein
Female
Indicators and Reagents
pharmacokinetics
metabolism
Bilirubin-glucuronoside glucuronosyltransferase
Zdroj: Hepatology (Baltimore, Md.), 33(3), 627-632. John Wiley and Sons Ltd
ISSN: 0270-9139
Popis: Although in Gilbert's syndrome (GS), bilirubin glucuronidation is impaired due to an extra TA in the TATA box of the promoter of the gene for bilirubin UDP-glucuronosyltransferase 1 (UGT1A1), many GS homozygotes lack unconjugated hyperbilirubinemia. Accordingly, an additional defect in bilirubin transport might be required for phenotypic expression. Plasma bilirubin and the early fractional hepatic uptake rate (BSP K(1)) of a low dose of tetrabromosulfophthalein (0.59 micromol/kg) were determined in (1) 15 unrelated patients with unconjugated hyperbilirubinemia plus 12 random controls; (2) 4 unrelated GS probands and 15 of their first-degree relatives; (3) 7 unrelated patients with hemolysis due to beta-Thalassemia minor. Subjects were classified by DNA sequencing of the promoter region of both UGT1A1 alleles. In group 1, GS homozygotes showed a highly significant negative linear correlation between plasma bilirubin levels and BSP K(1). BSP K(1) values overlapped considerably between GS and normal subjects, whereas, in group 2, they were clustered within, and sharply segregated among, families. Patients with hemolysis, despite elevated plasma bilirubin levels, had mean BSP K(1) values similar to the normal subjects. Within each GS subgroup with defined UGT1A1 mutations, the plasma bilirubin level is in part determined by the organic anion uptake rate, assessed by early plasma disappearance of low-dose BSP. The lower BSP uptake in GS is not secondary to the hyperbilirubinemia, but probably caused by (an) independent, genetically determined defect(s) in hepatic transport mechanism(s), shared by BSP and bilirubin, that are likely necessary for phenotypic expression of GS.
Databáze: OpenAIRE
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