HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

Abstract
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.
AuthorsM Persico, E Persico, C T Bakker, I Rigato, A Amoroso, R Torella, P J Bosma, C Tiribelli, J D Ostrow
JournalHepatology (Baltimore, Md.) (Hepatology) Vol. 33 Issue 3 Pg. 627-32 (Mar 2001) ISSN: 0270-9139 [Print] United States
PMID11230743 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Indicators and Reagents
  • Sulfobromophthalein
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Bilirubin
Topics
  • 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 (blood, metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: