Novel UDP-glucuronosyltransferase (UGT1A3) Polymorphisms with Varying Activity
|
Accession number;05A0094908
|
| Title;Novel UDP-glucuronosyltransferase (UGT1A3) Polymorphisms with Varying Activity |
| Author;
IWAI MASARU
(Shiga Univ. Medical Sci., Undergraduate School of Mediceine, JPN)
MORI ASAMI
(Shiga Univ. Medical Sci., Undergraduate School of Mediceine, JPN)
MARUO YOSHIHIRO
(Shiga Univ. Medical Sci., Undergraduate School of Mediceine, JPN)
TAKEUCHI YOSHIHIRO
(Shiga Univ. Medical Sci., Undergraduate School of Mediceine, JPN)
SATO HIROSHI
(Shiga Univ. Medical Sci., Undergraduate School of Mediceine, JPN)
|
Journal Title;Japanese Pharmacology & Therapeutics
|
Journal Code:Z0947A
|
ISSN:0386-3603
|
|
VOL.32;NO.Suppl.2;PAGE.S.183-S.188(2004)
|
| Figure&Table&Reference;FIG.2, TBL.2, REF.28 |
| Pub. Country;Japan |
| Language;Japanese |
| Abstract;Objective: Human UDP-glucuronosyltransferase (UGT) is part of a major excretion pathway for endobiotics and xenobiotics. The UGT family of genes is highly polymorphic, and our aim is to describe novel polymorphisms at the UGT1A3 locus and determine how they alter substrate metabolism and drug reactions. Method: Healthy 100 Japanese adults volunteered for the present study. We sequenced PCR-amplified fragments of the gene directly, and calculated the frequency of the mutations detected. To measure mutant enzyme activity, we constructed five expression models and used estrone as the substrate in the assays. Results: We identified 6 novel single nucleotide polymorphisms (SNPs). Of these, four caused amino acid substitutions (17A.RAR.G: Q6R, 31T.RAR.C: W11R, 133C.RAR.T: R45W, and 140T.RAR.C: V47A) and the remaining two were silent (81G.RAR.A: E27E and 447A.RAR.G: A159A). We found 5 types of alleles having differing SNP combinations wild type (frequency=0.61), W11R-E27E-A159A (0.10), Q6A-W11R-E27E-A159A (0.055), W11R-E27E-V47A-A159A (0.125), and R45W (0.11). Expression studies found that the mutations changed the enzyme efficiencies (Km/Vmax) to 121% of the wild type for W11R, 86% for Q6R-W11R, 369% for W11R-V47A, and 70% for R45W. Conclusion: Several UGT1A3 polymorphisms exist in the Japanese population, having different levels of activity. These polymorphisms are capable of affecting the steady state levels of estrogens, and may increase sensitivity to adverse drug effects. (author abst.) |
|
|
|
Related Articles;
|
|
