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Received for publication September 14, 2004.
Revised February 16, 2005.
Accepted for publication February 16, 2005.
UDP-glucuronosyltransferases (UGT) detoxify bilirubin and therapeutic drugs, a process influenced by single nucleotide polymorphisms (SNPs) in their structural genes and promoter elements. UGT1A1*28 is a functional UGT promoter polymorphism associated with Gilbert's disease and severe irinotecan toxicity, which also occurs in the absence of UGT1A1*28. The aim of this study was to identify and characterize UGT promoter variants with possible relevance for irinotecan detoxification. Recombinant UGT1A proteins were analyzed for irinotecan metabolite glucuronidation by UGT activity assays. In 427 healthy blood donors and 71 homozygous UGT1A1*28 carriers the 5'-untranslated region of the UGT1A7 gene was studied. A SNP was detected by allelic discrimination and characterized by reporter gene experiments. A novel -57 T>G SNP with a gene frequency of 0.39 in healthy blood donors was identified in the putative TATA box of the UGT1A7 gene reducing promoter activity to 30%. It is in linkage dysequilibrium with a variant of the UGT1A7 first exon present in the reduced activity UGT1A7*3 and UGT1A7*4 alleles. Homozygous UGT1A1*28 carriers simultaneously carried this variant in 98%. We identified a novel reduced function TATA box SNP of the UGT1A7 gene which catalyzes irinotecan metabolite detoxification. Its association with variants of the UGT1A1 promoter and UGT1A7 gene may influence irinotecan metabolism. Our finding emphasizes the importance of combinations of structural and regulatory gene polymorphisms which may be useful as a marker of drug toxicity.
Key words:
Promoter analysis, Genetics, Phase II enzymes, Regulation - transcriptional, UDP-glucuronyltransferases, Pharmacokinetics, metabolism and activation
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