Linked Life Data

16790554

Source:http://linkedlifedata.com/resource/pubmed/id/16790554

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2006-8-23
pubmed:abstractText
Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil (MMF), a standard immunosuppressive drug approved for clinical use in the prevention of acute allograft rejection after organ transplantation. This study examines the role of the genetic variants of UDP-glucuronosyltransferase (UGT) 1A8 and 2B7 enzymes involved in the formation of the primary metabolite of MPA, the inactive phenolic glucuronide (MPAG), and the reactive acyl glucuronide (AcMPAG). The first exon of UGT1A8 was first resequenced in the region encoding for the substrate binding domain in 254 Caucasians and 41 African Americans. Eight nonsynonymous changes were observed and led to the following amino acid substitutions: S43L, H53N, S126G, A144V, A173G, A231T, T240A, and C277Y. Thirteen haplotypes were inferred, comprising only two previously described alleles, namely, UGT1A8*2 (A173G) and UGT1A8*3 (C277Y). Upon stable expression in human embryonic kidney 293 cells, the UGT1A8*3 (C277Y), *5 (G173A240), *7 (A231T), *8 (S43L), and *9 (N53G) proteins were associated with the most profound decreases in the formation of MPAG and AcMPAG, indicating that these amino acids are critical for substrate binding and enzyme function. Altogether, the low-activity UGT1A8 enzymes are carried by 2.8 to 4.8% of the population. The variant of the UGT2B7 protein (UGT2B7*2 Y268), the main enzyme involved in the formation of AcMPAG, demonstrated a catalytic efficiency comparable with that of UGT2B7*1 (H268). In conclusion, although the common UGT2B7*2 variant is predicted to have limited impact, several UGT1A8 variants identified may potentially account for the large interindividual variance in MMF pharmacokinetics and deserve further clinical investigations.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
34
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1539-45
pubmed:meshHeading
pubmed-meshheading:16790554-Acylation, pubmed-meshheading:16790554-African Americans, pubmed-meshheading:16790554-Biotransformation, pubmed-meshheading:16790554-Cell Line, pubmed-meshheading:16790554-European Continental Ancestry Group, pubmed-meshheading:16790554-Gene Frequency, pubmed-meshheading:16790554-Glucuronides, pubmed-meshheading:16790554-Glucuronosyltransferase, pubmed-meshheading:16790554-Haplotypes, pubmed-meshheading:16790554-Humans, pubmed-meshheading:16790554-Immunosuppressive Agents, pubmed-meshheading:16790554-Intestines, pubmed-meshheading:16790554-Isoenzymes, pubmed-meshheading:16790554-Kinetics, pubmed-meshheading:16790554-Microsomes, pubmed-meshheading:16790554-Mutation, Missense, pubmed-meshheading:16790554-Mycophenolic Acid, pubmed-meshheading:16790554-Phenols, pubmed-meshheading:16790554-Polymorphism, Single Nucleotide, pubmed-meshheading:16790554-Sequence Analysis, DNA, pubmed-meshheading:16790554-Transfection
pubmed:year
2006
pubmed:articleTitle
Influence of nonsynonymous polymorphisms of UGT1A8 and UGT2B7 metabolizing enzymes on the formation of phenolic and acyl glucuronides of mycophenolic acid.
pubmed:affiliation
Canada Research Chair in Pharmacogenomics, Pharmacogenomics Laboratory, CHUL Research Center, T3-48, 2705 Boul. Laurier, QC, G1V 4G2, Canada.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't