Journal of Hepatology
Volume 33, Issue 3 , Pages 348-351, September 2000

Association of human liver bilirubin UDP-glucuronyltransferase activity with a polymorphism in the promoter region of the UGT1A1 gene

  • Maarten T.M Raijmakers

      Affiliations

    • Department of GastroenterologyThe Netherlands
    • ,
  • Peter L.M Jansen

      Affiliations

    • Department of Gastroenterology, University Hospital Groningen, The Netherlands
    • ,
  • Eric A.P Steegers

      Affiliations

    • Obstetrics and Gynaecology, University Hospital St. Radboud, Nijmegen,The Netherlands
    • ,
  • Wilbert H.M Peters

      Affiliations

    • Corresponding Author InformationWilbert H. M. Peters, Department of Gastroenterology, University Hospital St. Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: 31 24 3615123. Fax: 31 24 3540103.
    • Department of GastroenterologyThe Netherlands

Received 13 August 1999; received in revised form 2 December 1999; accepted 10 January 2000.

Abstract 

Background/Aims: Gilbert's syndrome is a benign form of a deficiency in bilirubin glucuronidation. It is associated with a homozygous polymorphism, A(TA)7TAA instead of A(TA)6TAA, in the TATA-box of the promoter region of the bilirubin UDP-glucuronyltransferase gene. In this study the correlation between this promoter region polymorphism and in vitro human liver bilirubin UDP-glucuronyltransferase enzyme activity was investigated.

Methods: Liver samples from organ transplant donors (n=39) and two known Gilbert's syndrome patients were used for measuring bilirubin UDP-glucuronyltransferase enzyme activity and for isolation of DNA followed by detection of the promoter region polymorphism by polymerase chain reaction. Genotypes were assigned as follows; 6/6: homozygous for the A(TA)6TAA-allele, 7/7: homozygous for the A(TA)7TAA-allele, and 6/7: heterozygous with one of each alleles.

Results: Seventeen out of 39 subjects (44%) had the homozygous 6/6 genotype, 18 subjects (46%) had the heterozygous 6/7 genotype, whereas four individuals (10%) and the two individuals with Gilbert's syndrome had the 7/7 genotype correlated with Gilber's syndrome. This resulted in an allele frequency of 0.33 for the A(TA)7TAA-allele. The median bilirubin UDP-glucuronyltransferase enzyme activity of the 17 subjects with the 6/6 genotype (1565 nmol/g liver/h) was significantly higher than the activity of the 18 subjects with the 6/7 genotype (985 nmol/g liver/h; p<0.05) and the six individuals with the 7/7 genotype (749 nmol/g liver/h; p<0.005). No significant differences in enzyme activity were found between the 6/7 and the 7/7 genotype groups.

Conclusions: The results indicate a close association between the promoter region genotype and the expression of hepatic bilirubin UDP-glucuronyltransferase enzyme activity. Subjects who have a 7/7 genotype have the lowest enzyme activity, whereas subjects with the heterozygous 6/7 genotype have an intermediate enzyme activity.

Keywords:  Bilirubin UDP-glucuronyltransferase, Gilbert's syndrome, Human liver, Polymorphism, UGT1A1

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PII: S0168-8278(00)80268-8

Journal of Hepatology
Volume 33, Issue 3 , Pages 348-351, September 2000

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