Meyer U A
Department of Pharmacology, Biocenter of the University of Basel, Switzerland.
Fundam Clin Pharmacol. 1990;4(6):595-615. doi: 10.1111/j.1472-8206.1990.tb00041.x.
The molecular mechanisms of 3 genetic polymorphisms of drug metabolism have been studied at the level of enzyme activity, enzyme protein and RNA/DNA. As regards debrisoquine/sparteine polymorphism, cytochrome P-450IID6 was absent in livers of poor metabolizers; aberrant splicing of premRNA of P-450IID6 may be responsible for this. Moreover, 3 mutant alleles of the P-450IID6 locus on chromosome 22 associated with the poor metabolizer phenotype were identified by Southern analysis of leucocyte DNA. The presence of 2 identified mutant alleles allowed the prediction of the phenotype in approximately 25% of poor metabolizers. The additional gene-inactivating mutations which are operative in the remainder of poor metabolizers are now being studied. Regarding mephenytoin polymorphism, although the deficient reaction, S-mephenytoin 4'-hydroxylation, has been well defined in human liver microsomes, the mechanism of this polymorphism remains unclear. All antibodies prepared to date against cytochrome P-450 fractions with this activity recognize several structurally similar enzymes and several cDNAs related to these enzymes have been isolated and expressed in heterologous systems. However, which isozyme is affected by this polymorphism is not known. As regards N-acetylation polymorphism, N-acetyltransferases have been purified from human liver, specific antibodies prepared; it was observed that immunoreactive N-acetyltransferase is decreased or undetectable in liver of "slow acetylators". Two genes that encode functional N-acetyltransferase were characterized. The product of one of these genes has identical activity and characteristics as the polymorphic liver enzyme. Cloned DNA from rapid and slow acetylator individuals has been analyzed to identify the structural or regulatory defect that causes deficient N-acetyltransferase.
已在酶活性、酶蛋白和RNA/DNA水平上研究了药物代谢的3种基因多态性的分子机制。关于异喹胍/司巴丁多态性，在代谢缓慢者的肝脏中未检测到细胞色素P - 450IID6；P - 450IID6前体mRNA的异常剪接可能是其原因。此外，通过对白细胞DNA的Southern分析，在22号染色体上鉴定出了与代谢缓慢者表型相关的P - 450IID6位点的3个突变等位基因。在大约25%的代谢缓慢者中，检测到的2个突变等位基因可用于预测表型。目前正在研究在其余代谢缓慢者中起作用的其他基因失活突变。关于美芬妥英多态性，尽管在人肝微粒体中已明确了缺陷反应，即S - 美芬妥英4'-羟化反应，但这种多态性的机制仍不清楚。迄今为止制备的所有针对具有该活性的细胞色素P - 450组分的抗体都识别几种结构相似的酶，并且已分离出与这些酶相关的几种cDNA并在异源系统中表达。然而，尚不清楚哪种同工酶受这种多态性影响。关于N - 乙酰化多态性，已从人肝脏中纯化了N - 乙酰转移酶，并制备了特异性抗体；观察到在“慢乙酰化者”的肝脏中，免疫反应性N - 乙酰转移酶减少或无法检测到。鉴定了两个编码功能性N - 乙酰转移酶的基因。其中一个基因的产物具有与多态性肝脏酶相同的活性和特性。已对快速和慢速乙酰化者个体的克隆DNA进行分析，以确定导致N - 乙酰转移酶缺陷的结构或调节缺陷。
