title: Association of human liver bilirubin UDP-glucuronyltransferase activity with a polymorphism in the promoter region of the UGT1A1 gene.
abstract: OBJECTIVE
  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 Gilbert'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.
authors.affiliation: Department of Gastroenterology, University Hospital St. Radboud, Nijmegen, The Netherlands.
authors.forename: M T
authors.initials: MT
authors.lastname: Raijmakers
authors.forename: P L
authors.initials: PL
authors.lastname: Jansen
authors.forename: E A
authors.initials: EA
authors.lastname: Steegers
authors.forename: W H
authors.initials: WH
authors.lastname: Peters
mesh_terms: D000483:Alleles; D005787:Gene Frequency; D005838:Genotype; D005878:Gilbert Disease / Q000201:enzymology / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000201:enzymology*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012016:Reference Values
chemical_list: D014453:Glucuronosyltransferase