TRANSCRIPTIONAL REGULATION OF GENES ENCODING XENOBIOTIC METABOLIZING ENZYMES

异生物质代谢酶负责代谢， 所有临床使用药物的灭活。他们还参与了 毒素、诱变剂和化学品的代谢活化或灭活 致癌物质。这些酶表达水平的显著差异 这些差异可能会导致 对药物和致癌物敏感性的个体差异。 不同的基因表达可以解释一些水平上的差异 外源物质代谢酶的表达。大多数酶 在肝脏中表达，它们的基因受 不同的肝细胞转录因子。几个家庭的 转录因子优先在肝脏中表达， 控制肝脏特异性基因表达。通常，体外技术， 包括报告基因构建体的转染和DNA结合 检测，用于研究基因调控。但很难 直接证明使用体外研究获得的结果 实际上反映了完整动物的基因表达。研究来 确定肝细胞富集因子是否参与调节 体内基因表达可以通过使用基因敲除来破坏 转录因子的表达，然后确定影响 靶基因表达的转录因子损失。但标 转录因子的基因敲除通常导致 胚胎前或胚胎后致死为了解决这个问题，老鼠 缺乏转录因子表达的基因正在使用 Cre/LoxP条件敲除系统。含有重组的小鼠 已经产生了位于C/EBPalpha基因侧翼的信号LoxP， 正常表型表明LoxP位点不干扰 基因表达。将Cre重组酶引入成年小鼠 含有LoxP-修饰的C/EBPalpha等位基因， 产生90%重组和C/EBPalpha缺失的腺病毒 肝脏中的基因。这导致了几个靶基因表达的缺失。 包括UDP-葡萄糖醛酸基转移酶UGT 1在内的基因， 胆红素结合。编码异生物质的其他基因的表达- 正在分析代谢酶

Xenobiotic-metabolizing enzymes are responsible for metabolism and inactivation of all clinically used drugs. They are also involved in the metabolic activation or inactivation of toxins, mutagens and chemical carcinogens. Marked differences in levels of expression of these enzymes have been found in humans and these differences could contribute to interindividual differences in sensitivities to drugs and carcinogens. Variable gene expression could account for some differences in levels of expression of xenobiotic-metabolizing enzymes. Most of these enzymes are expressed in the liver and their genes are under control of different hepatocyte transcription factors. Several families of transcription factors are preferentially expressed in the liver and control liver-specific gene expression. Typically, in vitro techniques, including transfections of reporter gene constructs and DNA binding assays, are used to study gene regulation. However, it is difficult to directly demonstrate that results obtained using in vitro studies actually reflect gene expression in the intact animal. Studies to determine whether hepatocyte-enriched factors are involved in regulating gene expression in vivo can be done by using gene knockouts to disrupt expression of transcription factors and then determine the effects transcription factor loss on target gene expression. However, standard gene knockouts of transcription factors frequently results in either pre- or post-embryonic lethality. To circumvent this problem, mice lacking transcription factor expression are being produced using the Cre/LoxP conditional knockout system. Mice containing the recombination signal LoxP flanking the C/EBPalpha gene have been produced and exhibit normal phenotypes indicating that the LoxP sites do not interfere with gene expression. The Cre recombinase was introduced to adult mice containing the LoxP-modified C/EBPalpha allele using a recombinant adenovirus yielding 90% recombination and deletion of the C/EBPalpha gene in liver. This resulted in loss of expression of several target genes including the UDP-glucuronosyltransferase, UGT1, responsible for conjugation of bilirubin. Expression of other genes encoding xenobiotic- metabolizing enzymes are being analyzed.