Molekulare Regulation der konstitutiven Expression von Cytochrom P450 3A4 und der Einfluss von MDR1 Haplotypen als neue Prinzipien für die Variabilität des Metabolismus von Arzneimitteln

药物从体内的消除主要是通过一种称为细胞色素P450(CYP)的酶在肝脏中的代谢降解来实现的。细胞色素3A4酶约占细胞色素总量的30%，参与约50%临床用药的代谢。人体组织中CYP3A4蛋白表达和活性的广泛个体间差异(高达90倍)导致药物代谢的临床相关变异，这可能导致治疗失败或药物不良反应。因此，本项目的目的是研究新的分子机制来调节个体基础细胞色素P3A4的表达。分子遗传学方法将被用来对负责调控CYP3A4表达的基因序列进行功能分析，并寻找调控该表达的核蛋白的新结合区域。为了确定它们的临床相关性，将确定这些蛋白的个体表达与人体肝脏中CYP3A4之间的关系。MDR1基因编码的P-糖蛋白等药物转运蛋白可能通过细胞内主动输出调节因子来影响细胞色素P3A4的表达。通过建立一个表达遗传MDR1变异的细胞模型，将确定这些变异对CYP3A4表达调节的影响。这些研究有望为预测药物代谢的变异性提供重要的新的分子原理，从而提高药物治疗的疗效和安全性。

The elimination of drugs from the body is mainly achieved by metabolic degradation in the liver mediated by a class of enzymes called cytochrome P450 (CYP). The enzyme CYP3A4 comprises about 30% of total cytochrome content and mediates the metabolism of about 50% of clinically used drugs. An extensive inter-individual variation of CYP3A4 protein expression and activity in human tissues (up to 90-fold) leads to a clinically relevant variability in drug metabolism which might either result in therapeutic failure or adverse drug effects. Therefore, the aim of this project is to investigate new molecular mechanisms for the regulation of the individual basal CYP3A4 expression. Molecular genetic methods will be used to functionally analyze the gene sequence responsible for the regulation of CYP3A4 expression and to identify new binding regions for nuclear proteins regulating the expression. To establish their clinical relevance, the relationship between the individual expression of these proteins and of CYP3A4 in human livers will be determined. Drug transport proteins like P-glycoprotein encoded by the MDR1 gene might influence the regulation of CYP3A4 expression by active cellular export of regulating factors. By creation of a cellular model expressing genetic MDR1 variants, the influence of these variants on the regulation of CYP3A4 expression will be determined. These investigations are expected to yield important new molecular principles for predicting the variability in drug metabolism in order to improve the therapeutic efficacy and the safety of drug treatment.