title: Identification and characterization of a functional TATA box polymorphism of the UDP glucuronosyltransferase 1A7 gene.
abstract: 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 relevant 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 locus was studied. An 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 that is present in the reduced-activity UGT1A7*3 and UGT1A7*4 alleles. Homozygous UGT1A1*28 carriers simultaneously carried this variant in 97%. We identified a novel reduced-function TATA box SNP of the UGT1A7 gene that 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 that may be useful as markers of drug toxicity.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany.
authors.forename: Tim O
authors.initials: TO
authors.lastname: Lankisch
authors.forename: Arndt
authors.initials: A
authors.lastname: Vogel
authors.forename: Stefan
authors.initials: S
authors.lastname: Eilermann
authors.forename: Anette
authors.initials: A
authors.lastname: Fiebeler
authors.forename: Britta
authors.initials: B
authors.lastname: Krone
authors.forename: Ayse
authors.initials: A
authors.lastname: Barut
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Christian P
authors.initials: CP
authors.lastname: Strassburg
mesh_terms: D001483:Base Sequence; D014453:Glucuronosyltransferase / Q000032:analysis / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic / Q000235:genetics*; D016385:TATA Box / Q000235:genetics*; D000099148:UGT1A1 Enzyme
chemical_list: D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme