The independent contribution of miRNAs to the missing heritability in CYP3A4/5 functionality and the metabolism of atorvastatin

摘要：

　　To evaluate the independent contribution of miRNAs to the missing heritability in CYP3A4/5 functionality and atorvastatin metabolism,the relationships among three levels of factors,namely(1)clinical characteristics,CYP3A4/5 genotypes,and miRNAs,(2)CYP3A4 and CYP3A5 mRNAs,and(3)CYP3A activity,as well as their individual impacts on atorvastatin metabolism,were assessed in 55 human liver tissues.MiR-27b,miR-206,and CYP3A4 mRNA respectively accounted for 20.0%,5.8%,and 9.5%of the interindividual variations in CYP3A activity.MiR-142 was an independent contributor to the expressions of CYP3A4 mRNA(partial R2 = 0.12,P = 0.002)and CYP3A5 mRNA(partial R2 = 0.09,P = 0.005)but not CYP3A activity or atorvastatin metabolism.CYP3A activity was a unique independent predictor of variability of atorvastatin metabolism,explaining the majority of the variance in reduction of atorvastatin(60.0%)and formation of ortho-hydroxy atorvastatin(78.8%)and para-hydroxy atorvastatin(83.9%).MiR-27b and miR-206 were found to repress CYP3A4 gene expression and CYP3A activity by directly binding to CYP3A4 3”-UTR,while miR-142 was found to indirectly repress CYP3A activity.Our study indicates that miRNAs play significant roles in bridging the gap between epigenetic effects and missing heritability in CYP3A functionality.

关键词： CYP3A genotype miRNA missingheritability atorvastatin

作者: Ju-E Liu Bin Ren Lan Tang Qian-Jie Tang Xiao-Ying Liu Xin Li Xue Bai Wan-Ping Zhong Jin-Xiu Meng Hao-Ming Lin Hong Wu Ji-Yan Chen Shi-Long Zhong

作者单位: Medical Research Center of Guangdong General Hospital,Guangdong Academy of Medical Sciences,Guangzho Department of Pharmacy,The First Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong 5100 Department of Pharmaceutics,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou Department of Pharmacy of Guangdong General Hospital,Guangdong Academy of Medical Sciences,Guangzhou Medical Research Center of Guangdong General Hospital,Guangdong Academy of Medical Sciences,Guangzho Medical Research Center of Guangdong General Hospital,Guangdong Academy of Medical Sciences,Guangzho Department of Pharmacy of Guangdong General Hospital,Guangdong Academy of Medical Sciences,Guangzhou Medical Research Center of Guangdong General Hospital,Guangdong Academy of Medical Sciences,Guangzho Department of Hepatobiliary Surgery,Sun Yat-Sen Memorial Hospital,Sun Yat-sen University,Guangzhou 5 Department of Pharmacy of Guangdong General Hospital,Guangdong Academy of Medical Sciences,Guangzhou

会议类型: 国内会议

会议名称: 2017年广东省药师周大会

会议地点: 广州

会议语种:英文

页码: 1-34

在线出版日期: 2016-12-17（万方平台首次上网日期，不代表论文的发表时间）