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

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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.