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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/24070
Title: Influence of mutations associated with Gilbert and Crigler-Najjar type II syndromes on the glucuronidation kinetics of bilirubin and other UDP-glucuronosyltransferase 1A substrates
Authors: Wandee Udomuksorn
David J. Elliot
Benjamin C. Lewis
Peter I. Mackenzie
Krongtong Yoovathaworn
John O. Miners
Flinders University
Mahidol University
Flinders Medical Centre
Keywords: Biochemistry, Genetics and Molecular Biology;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 1-Dec-2007
Citation: Pharmacogenetics and Genomics. Vol.17, No.12 (2007), 1017-1029
Abstract: OBJECTIVES: UGT1A1 coding region mutations, including UGT1A1*6 (G71R), UGT1A1*7 (Y486D), UGT1A1*27 (P229Q) and UGT1A1*62 (F83L), have been linked to Gilbert syndrome in Asian populations, whereas homozygosity for UGT1A1*7 is associated with the Crigler-Najjar syndrome type II. This work compared the effects of (a) the individual UGT1A1 mutations on the glucuronidation kinetics bilirubin, β-estradiol, 4-methylumbelliferone (4MU) and 1-naphthol (1NP), and (b) the Y486 mutation, which occurs in the conserved carboxyl terminal domain of UGT1A enzymes, on 4MU, 1NP and naproxen glucuronidation by UGT1A3, UGT1A6 and UGT1A10. METHODS: Mutant UGT1A cDNAs were generated by site-directed mutagenesis and the encoded proteins were expressed in HEK293 cells. The glucuronidation kinetics of each substrate with each enzyme were characterized using specific high-performance liquid chromatography (HPLC) methods. RESULTS: Compared with wild-type UGT1A1, in-vitro clearances for bilirubin, β-estradiol, 4MU and 1NP glucuronidation by UGT1A1*6 and UGT1A1*27 were reduced by 34-74%, most commonly as a result of a reduction in Vmax. However, the magnitude of the decrease in the in-vitro clearances varied from substrate to substrate with each mutant. The glucuronidation activities of UGT1A1*7 and UGT1A1*62 were reduced by >95%. Introduction of the Y486D mutation essentially abolished UGT1A6 and UGT1A10 activities, and resulted in 60-90% reductions in UGT1A3 in-vitro clearances. CONCLUSIONS: The glucuronidation of all UGT1A1 substrates is likely to be impaired in subjects carrying the UGT1A1*6 and UGT1A1*62 alleles, although the reduction in metabolic clearance might vary with the substrate. The Y486D mutation appears to greatly reduce most, but not all, UGT1A activities. © 2007 Lippincott Williams & Wilkins, Inc.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=34748822655&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/24070
ISSN: 17446880
17446872
Appears in Collections:Scopus 2006-2010

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