Document Detail


Structural heterogeneity at the UDP-glucuronosyltransferase 1 locus: functional consequences of three novel missense mutations in the human UGT1A7 gene.
MedLine Citation:
PMID:  11037804     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
One of the most important mechanisms involved in host defense against xenobiotic chemicals and endogenous toxins is the glucuronidation catalysed by UDP-glucuronosyltransferase enzymes (UGT). The role of genetic factors in determining variable rates of glucuronidation is not well understood, but phenotypic evidence in support of such variation has been reported. In the present study, six single nucleotide polymorphisms were discovered in the first exon of the UGT1A7 gene, which codes for the putative substrate-binding domain, revealing a high structural heterogeneity at the UGT1 gene locus. The new UGT1A7 proteins differ in their primary structure at amino acid positions 129, 131 and 208, creating four distinct UGT1A7 allelic variants in the human population: UGT1A7*1 (N129 R131 W208), *2 (K129 K131 W208), *3 (K129 K131 R208), and *4 (N129 R131 R208). In functional studies, HEK cells stably transfected to express the four allelic UGT1A7 variants exhibited significant differences in catalytic activity towards 3-, 7-, and 9-hydroxy-benzo(a)pyrene. UGT1A7*3 exhibited a 5.8-fold lower relative Vmax compared to wild-type *1, whereas *2 and *4 had a 2.6- and 2.8-fold lower relative Vmax than *1, respectively, suggesting that these mutations confer slow glucuronidation phenotype. Kinetic characterization suggested that these differences were primarily attributable to altered Vmax. Additionally, it suggested that each amino acid substitutions can independently affect the UGT1A7 catalytic activity, and that their effects are additive. The expression pattern of UGT1A7 studied herein and its catalytic activity profile suggest a possible role of UGT1A7 in the detoxification and elimination of carcinogenic products in lung. A population study demonstrated that a considerable proportion of the population (15.3%) was found homozygous for the low activity allele containing all three missense mutations, UGT1A7*3. These findings suggest that further studies are needed to investigate the impact of the low UGT1A7 conjugator genotype on individual susceptibility to chemical-induced diseases and responses to therapeutic drugs.
Authors:
C Guillemette; J K Ritter; D J Auyeung; F K Kessler; D E Housman
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Pharmacogenetics     Volume:  10     ISSN:  0960-314X     ISO Abbreviation:  Pharmacogenetics     Publication Date:  2000 Oct 
Date Detail:
Created Date:  2001-01-25     Completed Date:  2001-01-26     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9211735     Medline TA:  Pharmacogenetics     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  629-44     Citation Subset:  IM    
Affiliation:
Department of Biology and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, USA. chantal.guillemette@crchul.ulaval.ca
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MeSH Terms
Descriptor/Qualifier:
Base Sequence
Cell Line, Transformed
DNA Primers
Female
Genotype
Glucuronosyltransferase / genetics*,  metabolism
Humans
Kinetics
Male
Mutation, Missense*
Pedigree
Polymerase Chain Reaction
Chemical
Reg. No./Substance:
0/DNA Primers; EC 2.4.1.17/Glucuronosyltransferase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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