GENE STRUCTURE AND REGULATION OF N-NITROSODIMETHYLAMINE DEMETHYLASE

N-亚硝基二甲胺脱甲基酶（P-450 j）是一种主要的 人和大鼠肝脏亚硝胺代谢酶。 下 在某些饮食和病理生理条件下，这种酶可以 也见于肾和肺。 亚硝胺的代谢 P-450 j导致亲电中间体的产生 可以结合并突变DNA 调节这种水平 因此，酶可能在亚硝胺介导的 致癌作用 P-450 j在大鼠肝脏、肾脏和肝脏中可升高5至6倍。 肺通过管理乙醇。 此增加的原因是 转录后事件，因为P-450 j mRNA水平不 变化 在化学诱导的糖尿病大鼠中，P-450 j也是 明显升高;然而，这种增加伴随着 mRNA特异性地稳定在小鼠的肝、肺和肾中， 糖尿病大鼠 与此同时，这些后... 转录调节，P-450 j被转录激活 在发展过程中。 为了探索这一机制， 发育调控，大鼠和人类P-450 j基因， 首先分离并测序。 两个基因都含有9个外显子， 在紧接的上游具有相当大的核苷酸相似性， 它们的转录起始位点 这个地区可能是一个重要的 P-450 j基因中的顺式作用调节结构域。 分析 大鼠和人的P-450 j基因在发育过程中显示， 大鼠和人类基因上游的胞嘧啶是 特异性去甲基化与它们的发育一致 activation.

N-nitrosodimethylamine demethylase (P-450j) is a major nitrosamine metabolizing enzyme in human and rat liver. Under certain dietary and pathophysiologic conditions, this enzyme can also be found in kidney and lung. Metabolism of nitrosamines by P-450j results in the production of electrophilic intermediates that can bind and mutate DNA. Regulation of the levels of this enzyme, therefore, may be important in nitrosamine-mediated carcinogenesis. P-450j can be elevated five- to sixfold in rat liver, kidney and lung through administration of ethanol. This increase is due to post-transcriptional events since P-450j mRNA levels do not change. In the chemically induced diabetic rat, P-450j is also markedly elevated; however, this increase is accompanied by an mRNA is specifically stabilized in the liver, lung and kidney of the diabetic rat. In contrast to these instances of post- transcriptional regulation, P-450j is transcriptionally activated during development. To explore the mechanism of this developmental regulation, the rat and human P-450j genes were first isolated and sequenced. Both genes contain nine exons and share considerable nucleotide similarity immediately upstream of their transcription start sites. This region may be an important cis-acting regulatory domain in the P-450j gene. Analysis of the rat and human P-450j genes during development revealed that cytosines upstream of both the rat and human genes are specifically demethylated coincident with their developmental activation.