Abstract
The promoter polymorphisms of drug-metabolizing genes can lead to interindividual differences in gene expression, which may result in adverse drug effects and therapeutic failure. Based on the database of CYP2D6 gene polymorphisms in the Chinese Han population established by our group, we functionally characterized the single nucleotide polymorphisms (SNPs) of the promoter region and corresponding haplotypes in this population. Using site-directed mutagenesis, all the five SNPs identified and ten haplotypes with a frequency equal to or greater than 0.01 in the population were constructed on a luciferase reporter system. Dual luciferase reporter systems were used to analyze regulatory activity. The activity produced by Haplo3(−2183G>A, −1775A>G, −1589G>C, −1431C>T, −1000G>A, −678A>G), Haplo8(−2065G>A, −2058T>G, −1775A>G, −1589G>C, −1235G>A, −678A>G) and MU3(−498C>A) was 0.7−, 0.7−, 1.2− times respectively compared with the wild type in human hepatoma cell lines(p<0.05). These findings might be useful for optimizing pharmacotherapy and the design of personalized medicine.
Highlights
Cytochrome P450 CYP2D6, located on chromosome 22q13.2, codes for a major drug-metabolizing enzyme that plays a crucial role in the metabolism of several widely used therapeutic agents including cardiovascular drugs, b-adrenergic blocking agents, antidepressants, and miscellaneous compounds such as methoxy amphetamine, codeine, and dextromethorphan [1].There are many factors affecting differences in drug metabolism among individuals
Abnormal CYP2D6 activity can result in adverse drug effects and therapeutic failure, and CYP2D6 gene polymorphism analysis could play an important role in individualized drug treatment in the future
CYP2D6 is one of the most important phase I drug metabolizing enzymes, and it makes up only 1.5% of the total cytochrome P450 isoforms, it metabolises approximately 20% of marketed drugs [11]
Summary
Cytochrome P450 CYP2D6, located on chromosome 22q13.2, codes for a major drug-metabolizing enzyme that plays a crucial role in the metabolism of several widely used therapeutic agents including cardiovascular drugs, b-adrenergic blocking agents, antidepressants, and miscellaneous compounds such as methoxy amphetamine, codeine, and dextromethorphan [1]. There are many factors affecting differences in drug metabolism among individuals. One of the most important is the genetic polymorphism of cytochrome P450 genes or cytochrome P450 regulatory factors [2]. The polymorphism of the enzyme results in poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultraextensive metabolizers of CYP2D6 drugs [3]. Abnormal CYP2D6 activity can result in adverse drug effects and therapeutic failure, and CYP2D6 gene polymorphism analysis could play an important role in individualized drug treatment in the future
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