f373dd4d-4677-469c-86e6-f7d049014533
title
Variation of hepatic glucuronidation: Novel functional polymorphisms of the  UDP-glucuronosyltransferase UGT1A4 .
27b1f880-962b-4b38-9ad0-f1548c04181e
abstract
UDP-glucuronosyltransferases are a family of drug metabolizing enzymes contributing to hepatic drug metabolism and protection against environmental toxins. The aim of this study was to identify polymorphisms at the human UGT1A gene locus and to characterize their function and potential association with hepatocellular carcinoma (HCC). Genomic DNA from the blood of 363 subjects (128 patients with HCC, 235 blood donors) was analyzed for polymorphisms of the  UGT1A3 ,  UGT1A4 ,  UGT1A8 ,  UGT1A9 ,  UGT1A1 ,  UGT1A10  genes using polymerase chain reaction, sequencing analysis. Recombinant variant UGT protein was analyzed by activity assays. In the  UGT1A8  gene an  A173G  variant and a conserved  G to A exchange at position 765  were detected in 25% and 15%.  UGT1A9  exhibited two variants  C3Y  and  M33T  in 1% and 3%.  UGT1A1 ,  UGT1A10  exhibited conserved nucleotide exchanges ( 128 G-->A  and  696 C-->T ) in 2% and 13%. In the  UGT1A3  gene a  W11R , a  V47A  variant, and a conserved  G to A exchange at position 81  with an incidence of 65%, 58%, and 65%, respectively, were identified.  UGT1A4  exhibited a  P24T  and an  L48V  variant in 8% and 9%. UGT1A SNPs were not associated with HCC.  UGT1A4   P24T  and  L48V  exhibited reduced glucuronidation activities: beta-naphthylamine 30% and 50%, and dihydrotestosterone 50% and 0%, respectively. In conclusion, the high prevalence of SNPs throughout the human UGT1A gene locus illustrates a genetic basis of interindividual variations of hepatic metabolism. Two polymorphisms of the hepatic  UGT1A4  protein show a differential metabolic activity toward mutagenic amines and endogenous steroids, altering hepatic metabolism and detoxification.