Aryl hydrocarbon receptor-mediated regulation of the human estrogen and bile acid UDP-glucuronosyltransferase 1A3 gene

被引：36

作者：

Lankisch, Tim O. ^{[1
]}

Gillman, Tracey C. ^{[1
]}

Erichsen, Thomas J. ^{[1
]}

Ehmer, Ursula ^{[1
]}

Kalthoff, Sandra ^{[1
]}

Freiberg, Nicole ^{[1
]}

Munzel, Peter A. ^{[2
]}

Manns, Michael P. ^{[1
]}

Strassburg, Christian P. ^{[1
]}

机构：

[1] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, D-30625 Hannover, Germany

[2] Univ Tubingen, Dept Toxicol, Inst Pharmacol & Toxicol, Tubingen, Germany

来源：

ARCHIVES OF TOXICOLOGY | 2008年 / 82卷 / 09期

关键词：

UDP glucuronosyltransferase; transcriptional regulation; dioxin; single nucleotide polymorphism; UGT1A3; xenobiotic response element; aryl hydrocarbon receptor;

D O I：

10.1007/s00204-008-0347-1

中图分类号：

R99 [毒物学（毒理学）];

学科分类号：

100405 ;

摘要：

UDP-glucuronosyltransferases contribute to the detoxification of drugs by forming water soluble beta-d-glucopyranosiduronic acids. The human UGT1A3 protein catalyzes the glucuronidation of estrogens, bile acids and xenobiotics including non-steroidal anti-inflammatory drugs and lipid lowering drugs. Regulation of UGT1A3 by xenobiotic response elements is likely, but the responsible elements are yet uncharacterized. In addition, genetic promoter variants may affect UGT1A3 regulation and potential induction by xenobiotics. The UGT1A3 promoter was analyzed by mutagenesis, reporter gene, and mobility shift analyses. Three hundred and eighty-nine blood donors were genotyped for promoter single nucleotide polymorphisms (SNPs) showing an allelic frequency of 42% of variants at -66 (T to C) and -204 (A to G). A xenobiotic response element regulating aryl hydrocarbon receptor (AhR)-mediated UGT1A3 transcription was identified and characterized. UGT1A3 transcription was reduced in the presence of promoter SNPs. These data demonstrate xenobiotic induced regulation of the UGT1A3 gene by the AhR, which shows genetic variability.

引用

页码：573 / 582

页数：10

共 35 条

[1] Mechanism of rat UDP-glucuronosyltransferase 1A6 induction by oltipraz: Evidence for a contribution of the aryl hydrocarbon receptor pathway [J].

Auyeung, DJ ;

Kessler, FK ;

Ritter, JK .

MOLECULAR PHARMACOLOGY, 2003, 63 (01) :119-127

[2] Activation of the mouse TATA-less and human TATA-containing UDP-glucuronosyltransferase 1A1 promoters by hepatocyte nuclear factor 1 [J].

Bernard, P ;

Goudonnet, H ;

Artur, Y ;

Desvergne, B ;

Wahli, W .

MOLECULAR PHARMACOLOGY, 1999, 56 (03) :526-536

[3]

BLUMENFELD M, 1991, DEVELOPMENT, V113, P589

[4] THE GENETIC-BASIS OF THE REDUCED EXPRESSION OF BILIRUBIN UDP-GLUCURONOSYLTRANSFERASE-1 IN GILBERTS-SYNDROME [J].

BOSMA, PJ ;

CHOWDHURY, JR ;

BAKKER, C ;

GANTLA, S ;

DEBOER, A ;

OOSTRA, BA ;

LINDHOUT, D ;

TYTGAT, GNJ ;

JANSEN, PLM ;

ELFERINK, RPJO ;

CHOWDHURY, NR .

NEW ENGLAND JOURNAL OF MEDICINE, 1995, 333 (18) :1171-1175

[5] A pharmacogenomics study of the human estrogen glucuronosyltransferase UGT1A3 [J].

Caillier, Bertrand ;

Lepine, Johanie ;

Tojcic, Jelena ;

Menard, Vincent ;

Perusse, Louis ;

Belanger, Alain ;

Barbier, Olivier ;

Guillemette, Chantal .

PHARMACOGENETICS AND GENOMICS, 2007, 17 (07) :481-495

[6] Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus [J].

Chen, SJ ;

Beaton, D ;

Nguyen, N ;

Senekeo-Effenberger, K ;

Brace-Sinnokrak, E ;

Argikar, U ;

Remmel, RP ;

Trottier, J ;

Barbier, O ;

Ritter, JK ;

Tukey, RH .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (45) :37547-37557

[7] Genetic variants of human UGT1A3: Functional characterization and frequency distribution in a Chinese Han population [J].

Chen, Yakun ;

Chen, Shuqing ;

Li, Xin ;

Wang, Xiewei ;

Zeng, Su .

DRUG METABOLISM AND DISPOSITION, 2006, 34 (09) :1462-1467

[8] Variation of hepatic glucuronidation:: Novel functional polymorphisms of the UDP-glucuronosyltransferase UGT1A4 [J].

Ehmer, U ;

Vogel, A ;

Schütte, JK ;

Krone, B ;

Manns, MP ;

Strassburg, CP .

HEPATOLOGY, 2004, 39 (04) :970-977

[9]

Emi Y, 1996, J BIOL CHEM, V271, P3952, DOI 10.1074/jbc.271.7.3952

[10] Isolation of the UDP-glucuronosyltransferase 1A3 and 1A4 proximal promoters and characterization of their dependence on the transcription factor hepatocyte nuclear factor 1α [J].

Gardner-Stephen, Dione A. ;

Mackenzie, Peter I. .

DRUG METABOLISM AND DISPOSITION, 2007, 35 (01) :116-120

← 1 2 3 4 →