DRUG METABOLIZING ENZYMES IN ANIMAL MODELS AND HUMAN TISSUE

细胞色素P-450系统是主要的单加氧酶系统 它将外来化学物质代谢成两种不活跃的化合物 以及激活它们对诱变剂和致癌物的作用。其中一些 酶在人类和啮齿动物中都是多态的。A多态 在与大鼠肝脏P-450(HP1-1)免疫化学相关的人P-450(HP1-1)中 最近有报道称有450克。这个P-450似乎存在 1约占人口的50%，其余人口中没有。 大鼠似乎是一个很好的人类模型，因为大鼠P-450G 也存在于50%的人口中，而在 余数。为了获得进一步研究的分子探针 在大鼠和人类中，这种缺陷是从一个高水平的 450g大鼠。用特异性抗体鉴定了几个cDNA P-450g。P-450G的全长cDNA已完全完成 已排序。这种细胞色素含有相当大的同源性 P-450IIc亚家族中的其他细胞色素以及 人类P-450、HP1-1。根据计算机分析，一个特定的 选择P-450G基因的寡核苷酸区域用于 北方人和南方人。该寡核苷酸探针证实了P-450G在 多态大鼠。然而，对+g和+g中RNA的Northern分析 -g组大鼠脑内+g和-9m RNA含量无明显差异 表型表明-g鼠可能包含一种替代的， 也许是有缺陷的信使核糖核酸。正在进行的其他研究包括 胎儿和新生儿的发育及其确定的研究 是否有任何肝外组织(更容易从人类身上研究) 含有这种核糖核酸。从-g中构建了cdna文库。 雄性大鼠，以及几个可能的克隆已经通过 杂交研究。这些克隆目前正在进行测序 以确定它们是否有缺陷，并开发 寡核苷酸探针，使我们能够区分+g和 -g表型。我们正在获取人类肝脏 用于研究人类P-450G可能作用的样本 同源基因是肝癌的危险因素。

The cytochrome P-450 system is the principal monooxygenase system which metabolizes foreign chemicals to both inactive compounds as well as activating them to mutagens and carcinogens. Some of these enzymes are polymorphic in both man and rodents. A polymorphism in a human P-450 (Hp1-1) immunochemically related to rat liver P- 450g has recently been reported. This P-450 appears to be present 1 about 50% of the human population and absent in the remainder. The rat appears to be a good model for the human since rat P-450g is also present in 50% of the population and absent in the remainder. In order to obtain molecular probes to further study this defect in rats and humans, a cDNA library was made from a high 450g rat. Several cDNAs were identified with specific antibody to P-450g. A full-length cDNA for P-450g has been completely sequenced. This cytochrome contains considerable homology to other cytochromes in the P-450IIc subfamily and to the cDNA for the human P-450, Hp1-1. Based on computer analysis, a specific oligonucleotide region of the P-450g cDNA was selected for use in Northerns and Southerns. This oligoprobe confirmed the P-450g in polymorphism rats. However, Northern analysis of RNA from +g and -g rats revealed no difference in mRNA content of +g and -9 phenotypes suggesting that -g rats might contain an alternate, perhaps defective mRNA. Additional studies underway include development in the fetus and neonate and studies to determine whether any extraheptic tissues (more readily studied from humans) contain this RNA. A cDNA library has been constructed from -g male rats, and several putative clones have been selected by hybridization studies. These clones are presently being sequenced to determine whether they are defective, and to develop oligonucleotide probes to allow us to differentiate between +g and -g phenotypes. We are in the process of obtaining human liver samples to investigate the possible role of the human P-450g homolog as a risk factor for liver cancer.