title: Regulation of cytochrome P450 3A4 by small vault RNAb derived from the non-coding vault RNA1 of multidrug resistance-linked vault particle.
abstract: Cytochrome P450 3A4 (CYP3A4) is the most abundant cytochrome P450 enzyme in human liver and intestine, contributing to the metabolism of >60% of all pharmaceuticals. The expression levels of hepatic CYP3A4 show great inter‑individual variation. However, the detailed regulatory mechanism of CYP3A4 expression has remained largely elusive. It has been reported that the non‑coding RNA small vault (sv)RNAb targets the 3' untranslated region (3'UTR) of CYP3A4 in MCF7 cells. However, to date, the role of svRNAb has not been examined in human liver tissue and hepatic cell lines such as HepG2, which was the aim of the present study. Polymerase chain reaction analysis indicated that the expression of CYP3A4 was significantly different within a study cohort (n=19). In addition, a significant negative correlation was observed between svRNAb and CYP3A4 expression in human liver tissue samples. Furthermore, a luciferase assay on HepG2 cells verified that svRNAb directly targets CYP3A4 and regulates the expression of CYP3A4 by interacting with the validated binding sites of the CYP3A4 3'UTR. The results provided insight into the variation of the expression of CYP3A4 among individuals and provided a novel method for the adjustment of personalized drug treatment. Furthermore, the present study provided a mechanism of the regulatory role of svRNAb in multidrug‑resistant cells.
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Chunjie
authors.initials: C
authors.lastname: Meng
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan 450006, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan 450006, P.R. China.
authors.forename: Hang
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan 450006, P.R. China.
authors.forename: Lirong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Qinghe
authors.initials: Q
authors.lastname: Xing
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008954:Models, Biological; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D058727:RNA, Small Untranslated / Q000235:genetics*; D020394:Vault Ribonucleoprotein Particles / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D058727:RNA, Small Untranslated; D020394:Vault Ribonucleoprotein Particles; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human