title: The effect of microRNAs in the regulation of human CYP3A4: a systematic study using a mathematical model.
abstract: CYP3A4 metabolizes more than 50% of the drugs on the market. The large inter-individual differences of CYP3A4 expression may contribute to the variability of human drug responses. Post-transcriptional regulation of CYP3A4 is poorly understood, whereas transcriptional regulation has been studied much more thoroughly. In this study, we used multiple software programs to predict miRNAs that might bind to CYP3A4 and identified 112 potentially functional miRNAs. Then a luciferase reporter system was used to assess the effect of the overexpression of each potentially functional miRNA in HEK 293T cells. Fourteen miRNAs that significantly decreased reporter activity were measured in human liver samples (N = 27) as candidate miRNAs. To establish a more effective way to analyze in vivo data for miRNA candidates, the relationship between functional miRNA and target mRNA was modeled mathematically. Taking advantage of this model, we found that hsa-miR-577, hsa-miR-1, hsa-miR-532-3p and hsa-miR-627 could significantly downregulate the translation efficiency of CYP3A4 mRNA in liver. This study used in silico, in vitro and in vivo methods to progressively screen functional miRNAs for CYP3A4 and to enhance our understanding of molecular events underlying the large inter-individual differences of CYP3A4 expression in human populations.
authors.affiliation: 1] Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China [2].
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Wei
authors.affiliation: 1] State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, PR China [2].
authors.forename: Songshan
authors.initials: S
authors.lastname: Jiang
authors.affiliation: 1] Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China [2] Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, PR China.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou 450052, PR China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Xueling
authors.initials: X
authors.lastname: Peng
authors.affiliation: 1] Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China [2] Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, PR China.
authors.forename: Chunjie
authors.initials: C
authors.lastname: Meng
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, PR China.
authors.forename: Yichen
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1] Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China [2] Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, PR China.
authors.forename: Honglian
authors.initials: H
authors.lastname: Wang
authors.affiliation: 1] Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China [2] Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, PR China.
authors.forename: Luo
authors.initials: L
authors.lastname: Guo
authors.affiliation: 1] Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China [2] Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, PR China.
authors.forename: Shengying
authors.initials: S
authors.lastname: Qin
authors.affiliation: 1] Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China [2] Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Urology, People's Hospital of Henan Province, Zhengzhou 450003, PR China.
authors.forename: Fengmin
authors.initials: F
authors.lastname: Shao
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou 450052, PR China.
authors.forename: Lirong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China.
authors.forename: Qinghe
authors.initials: Q
authors.lastname: Xing
mesh_terms: D001665:Binding Sites; D019295:Computational Biology / Q000379:methods; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D008099:Liver / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008962:Models, Theoretical; D034622:RNA Interference
chemical_list: D035683:MicroRNAs; D051544:Cytochrome P-450 CYP3A