Pharmacogenetics of human cytochromes P450

药物代谢是人体内各种药物作用的主要决定因素之一。大约40%的依赖细胞色素P450(CYP)的药物代谢是由多态酶执行的，由于等位基因变异的存在，这些多态酶表现出很大的遗传决定的个体间和种族间的代谢能力差异，导致酶活性的取消、定性或定量改变或增强。药物代谢的这种差异可能会导致药物反应不充分，如果是由于基因复制或多重复制而导致的超快代谢，或者是由于等位基因缺陷而导致代谢下降的严重不良反应。本应用的总体目的是研究由细胞色素P450酶催化的药物代谢的个体间和种族间差异的分子遗传学和酶基础，并评估这种差异对不同种族的重要药物的药代动力学和临床效果的影响。特别致力于开发和评估用于预测酶活性的基因分型和表型方法，从而预测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，使药物治疗更有效、更安全，既适用于个别患者，也适用于不同人群，同时考虑到不同种族之间的问题。该项目应用细胞色素P450基因(CyP1b1、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对体外表达系统中药物代谢的功能影响，开发用于评估人类体内酶活性的表型方法，并评估不同种族的基因-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，研究了由基因和表型分析确定的个体间和种族间变异性对由多态P450代谢的模型药物的药代动力学和临床效果的临床意义。该项目结合了分子药理学和临床药理学对人体药物代谢和药物作用的评估。

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.