Systematic Functional Study Of Cytochrome P4502d6Promoter Polymorphisms In The Chinese Han Population

CYP450is important drug metabolism enzyme, which can catalyze drug,environmental carcinogen, chemical poison and endogenic substances.CYP450makes the liver have the feature of disintoxication．P450genestructure is of highly polymorphism, which can lead to metabolic dysfunctionof the enzyme, resulting in the loss of enzyme activity, decreased or increasedthus causing the corresponding change in the drug metabolism andconsequently the failure of the treatment, individual Adverse Drug Reaction(ADR) and even death. CYP2D6is the most polymorphism enzyme inCYP450superfamily, which makes up only1.5%of the total cytochromeP450isoforms, and metabolises approximately25%of marketed drugs. So, itis necessary to have study about relationship between gene polymorphismand gene expression.Based on the database of CYP2D6gene polymorphisms in Chinese Hanpopulation (-2183G>A,-2065G>A,-2058T>G,-1775A>G,-1589G>C, -1431C>T,-1235G>A,-1000G>A,-741C>T,-678A>G,-528C>T,-498C>A,-345T>C,-336A>G) established by our group, five SNPs (741C>T,528C>T,498C>A,345T>C,336A>G) and ten haplotypes(AAGGCCAGCGCCTA，AGTGCTGGCGCCTA，AGTGCTGACGCCTA，AGTGCCGGTACCTA，AGTGCCGACGCCTA，AGTGCCAACGCCTA，GAGGCCAGCGCATA，GAGGCCAGCGCCTA，GGTACCGGTACCTA，GGTGCTGACGCCTA) with a frequency equal to or greater than0.01inChinese Han people were established on a luciferase reporter system.Dual luciferase reporter systems were used to analyze regulatory activity.The results indicated that the constructs includingHaplo3(AGTGCTGACGCCTA) and Haplo8(GAGGCCAGCGCCTA),exhibited down regulation on luciferase activity in comparison with thesample without variation, and reduced regulatory activity25.66%(p=0.003465)，31.33%(p=0.000139) respectively. This might lead to lowerCYP2D6activity on drug metabolism, Whereas the single point mutationsMU3(-498C>A) exhibited up regulation of luciferase activity compared withthe wild type construct, increased the regulatory activity23.43%(p=0.016227). The individuals carrying the SNP might have a faster CYP2D6drug metabolism and a higher risk of xenobiotics-induced liver injury ascompared to wild type carriers. In conclusion, this is the first study to carry out a systematicallyfunctional characterization of the promoter region of CYP2D6variants in theChinese Han population. These results would be a basal research on CYP2D6phenotype characterization and be useful for optimizing pharmacotherapyand the design for individualized pharmaceutical in Chinese population.