Pharmacogenetics of human cytochromes P450

药物代谢是人体内药物作用变化的主要决定因素之一。大约40%的人类细胞色素P450 （CYP）依赖的药物代谢是由多态性酶进行的，由于等位基因变异的存在，导致酶活性的消除、定性或定量改变或增强，在个体间和种族间表现出很大的遗传决定的代谢能力变异性。这种药物代谢的差异可能会导致基因复制或多重复制等导致的超快速代谢导致药物反应不足，也可能导致等位基因缺陷导致代谢降低而产生严重的不良反应。本申请的总体目的是研究细胞色素P450酶催化药物代谢的个体间和种族间差异的分子遗传学和酶学基础，并评估这种差异对不同种族重要药物的药代动力学和临床疗效的影响。特别努力放在开发和评估基因分型和表型方法预测酶活性，从而，模型药物的药代动力学和临床效果。所获得的知识将构成个体化药物剂量的基础，在考虑到种族间因素的情况下，允许对个别病人和不同人群进行更有效和更安全的药物治疗。该项目应用细胞色素P450基因（CYP 1B1、2A6和3A4）的分子遗传学分析来检测新的等位基因变异，分析新的和早期发现的突变在体外表达系统中对药物代谢的功能影响，开发用于评估人体内酶活性的表型方法，以及评估不同种族群体的基因型-表型关系。在健康志愿者和接受治疗剂量药物治疗的患者中，研究了由多态p450代谢的模型药物的药代动力学和临床效果，由基因和表型决定的个体间和种族间变异性的临床意义。该项目结合了分子药理学和药物代谢和药物在人体内作用的临床药理评估。

Drug metabolism is one of the major determinants of variable drug action in man. Approximately 40 percent of human cytochrome P450 (CYP)-dependent drug metabolism is carried out by polymorphic enzymes exhibiting large genetically determined interindividual and interethnic variability in metabolic capacity due to the presence of allelic variants causing abolished, qualitatively or quantitatively altered, or enhanced enzyme activity. Such differences in drug metabolism may result in inadequate drug response in case of ultrarapid metabolism due to, e.g. gene duplication or multiduplication, or serious adverse effects in case of decreased metabolism due to defective alleles. The overall aim of the present application is to study the molecular genetic and enzymatic basis of interindividual and interethnic differences in drug metabolism catalysed by cytochrome P450 enzymes, and to evaluate the implications of such variability for the pharmacokinetics and clinical effects of important drugs in different ethnic groups. Special effort is placed on development and evaluation of genotyping and phenotyping methods for prediction of enzyme activity, and consequently, the pharmacokinetics and clinical effects of model drugs. The knowledge acquired will constitute a basis for individualised drug dosage, allowing more efficient and safer drug treatment, both for individual patients and different populations, taking the interethnic aspects into account. The project applies molecular genetic analysis of cytochrome P450 genes (CYP 1B1, 2A6, and 3A4) for detection of new allelic variants, analysis of the functional consequences of new and earlier identified mutations for drug metabolism in in vitro expression systems, development of phenotyping methods for assessment of enzyme activity in vivo in man, and evaluation of the genotype-phenotype relationships in different ethnic groups. The clinical implications of interindividual and interethnic variability, as determined by geno- and phenotyping, for the pharmacokinetics and clinical effects of model drugs metabolised by the polymorphic P450s are studied in healthy volunteers and patients treated with therapeutic doses of the drugs. The project combines molecular pharmacogenetic and clinical pharmacological assessment of drug metabolism and drug action in man.