POLYMORPHIC DRUG OXIDATION--THE HUMAN AND RAT DEBRISOQUINE 4-HYDROXYLASE GENES

人类多形性药物氧化已被认识到 30年了。研究最广泛的是去氢异喹-4- 6%到8%的高加索人的羟基酶多态性 欧洲和北美的人口无法代谢这一点 毒品。我们实验室和其他实验室的研究证实了这一点 多态是由细胞色素P-450引起的。我们已经隔离了 并产生了抗鼠去氢异喹4-羟基酶的抗体 (DB1)，并用该抗体获得大鼠和人 CDNA克隆。这些都是经过测序的，与 已知的P-450序列和DB1构成了 分离P-450基因亚家族。基因克隆揭示了AT 至少存在四个与DB1相关的活性基因，并在 大鼠；这些基因中只有一个可能含有脱异喹羟基酶 活动。相比之下，在人类中，只有一个活跃的基因和 假基因存在。人类基因的克隆和测序 不具有DB1蛋白的肝脏显示存在 突变基因。三个突变基因的特征是 产生错误剪接的mRNA。DB1探测器可能会很有用 用于分析和检测人类群体中的突变基因。

Human polymorphic drug oxidation has been recognized for over 30 years. The most extensively studied is the debrisoquine 4- hydroxylase polymorphism in which 6% to 8% of the Caucasian population in Europe and North America cannot metabolize this drug. Studies in our lab and others confirmed that this polymorphism is due to a cytochrome P-450. We have isolated and produced antibody against the rat debrisoquine 4-hydroxylase (db1) and this antibody was used to obtain the rat and human cDNA clones. These were sequenced and, by comparison to the known P-450 sequences and db1, were found to constitute a separate P-450 gene subfamily. Gene cloning revealed that at least four active genes related to db1 exist and are expressed in rat; only one of these genes may have debrisoquine hydroxylase activity. In contrast, in humans, only one active gene and pseudogene exist. Cloning and sequencing of genes from human livers that do not possess the db1 protein revealed the presence of mutant genes. Three mutant genes were characterized that produce incorrectly spliced mRNA. The db1 probe may be useful for analysis and detection of mutant genes in human populations.