Lankisch Tim O, Gillman Tracey C, Erichsen Thomas J, Ehmer Ursula, Kalthoff Sandra, Freiberg Nicole, Munzel Peter A, Manns Michael P, Strassburg Christian P
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl Neuberg Strasse 1, Hannover, Germany.
Arch Toxicol. 2008 Sep;82(9):573-82. doi: 10.1007/s00204-008-0347-1. Epub 2008 Aug 2.
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.
UDP-葡萄糖醛酸基转移酶通过形成水溶性的β-D-吡喃葡萄糖醛酸来促进药物解毒。人类UGT1A3蛋白催化雌激素、胆汁酸和包括非甾体抗炎药及降脂药在内的外源性物质的葡萄糖醛酸化反应。外源性反应元件对UGT1A3的调控很可能存在，但相关元件尚未明确。此外，基因启动子变异可能影响UGT1A3的调控以及外源性物质对其的潜在诱导作用。通过诱变、报告基因和迁移率变动分析对外源性反应元件对UGT1A3的调控进行了分析。对389名献血者进行了启动子单核苷酸多态性（SNP）基因分型，结果显示-66（T到C）和-204（A到G）位点变异的等位基因频率为42%。鉴定并表征了一个调控芳烃受体（AhR）介导的UGT1A3转录的外源性反应元件。启动子SNP存在时，UGT1A3转录减少。这些数据表明AhR对外源性物质诱导的UGT1A3基因具有调控作用，且存在遗传变异性。
