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

Background/Aims: Gilbert's syndrome is a benign form of a deficiency in bil irubin glucuronidation. It is associated with a homozygous polymorphism, A( TA)(7)TAA instead of A(TA)(6)TAA, in the TATA-box of the promoter region of the bilirubin UDP-glucuronyltransferase gene. In this study the correlatio n between this promoter region polymorphism and ill vitro human liver bilir ubin UDP-glucuronyltransferase enzyme activity was investigated. Methods: Liver samples from organ transplant donors (n=39) and two known Gi lbert's syndrome patients were used for measuring bilirubin UDP-glucuronylt ransferase enzyme activity and for isolation of DIVA followed by detection of the promoter region polymorphism by polymerase chain reaction. Genotypes were assigned as follows; 6/6: homozygous for the A(TA)(6)TAA-allele, 7/7: homozygous for the A(TA)(7)-/TAA-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 individ uals (10%) and the two individuals with Gilbert's syndrome had the 7/7 geno type correlated with Gilbert's syndrome. This resulted in an allele frequen cy of 0.33 for the A(TA)(7)TAA-allele. The median bilirubin UDP-glucuronylt ransferase enzyme activity of the 17 subjects with the 6/6 genotype (1565 n mol/g liver/h) was significantly higher than the activity of the 18 subject s with the 6/7 genotype (985 nmol/g liver/h; p<0.05) and the six individual s with the 7/7 genotype (749 nmol/g liver/h; p<0.005), No significant diffe rences in enzyme activity were found between the 6/7 and the 7/7 genotype g roups. Conclusions: The results indicate a close association between the promoter region genotype and the expression of hepatic bilirubin UDP-glucuronyltrans ferase enzyme activity. Subjects who have a 7/7 genotype have the lowest en zyme activity, whereas subjects with the heterozygous 6/7 genotype have an intermediate enzyme activity.