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

Abstract

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.

3D Adipose Tissue Culture Links the Organotypic Microenvironment to Improved Adipogenesis

“…Notably, these effects were substantially more pronounced in 3D culture compared to differentiation in conventional 2D monolayers. Similarly, SOX2 and SOX9, which are required for the maintenance of proliferative, PDGFR α ‐positive adipose precursors, [ 55 , 56 ] and the Notch signaling effector RBPJ κ , a key factor in adipocyte dedifferentiation, [ 57 ] were strongly reduced in both 2D and 3D differentiated cells compared to preadipocytes. Pref‐1 (encoded by DLK1; compare Figure 2C ) and its direct interaction with fibronectin activates SOX9, jointly acting as a central gatekeeper for adipocyte differentiation, [ 56 , 58 ] thus molecularly linking the low‐fibronectin microenvironment in 3D culture to improved adipogenesis.…”

UGT1A1 rs4148323 A Allele is Associated With Increased 2-Hydroxy Atorvastatin Formation and Higher Death Risk in Chinese Patients With Coronary Artery Disease

“…Specimens for microsome extraction were quickly prepared using the GENMED A Solution (GENMED Scientific Inc., Arlington, TX, United States) and stored in liquid nitrogen until use. HLM were prepared according to our previously published protocol ( Liu et al, 2016 ). Protein concentration was determined by the Bradford protein assay kit (Bio-Rad, Hercules, CA, United States) with bovine serum albumin as standard.…”

The Roles of microRNAs in Cancer Multidrug Resistance

“…Overexpression of human miRNA-27b or mouse micro-RNA298 (mmu-miRNA298) in LS-180 and PANC1 cell lines reduced CYP3A4 expression by more than 30% and at the same time reduced the sensitivity of cells to cyclophosphamide [ 120 ]. Liu et al [ 121 ] showed that miRNA-27b may also affect the metabolism of atorvastatin (a blood cholesterol-lowering medicine) in the liver. Nevertheless, statins are not commonly accepted as anticancer drugs, and Jones et al [ 122 ] have shown that statins affect proliferation and metastasis in ovarian cancer.…”

“…Overexpression of miRNA-148a reduces PXR protein levels, thereby attenuating CYP3A4 mRNA induction [ 123 ]. MiRNA-206, which suppresses CYP3A4 expression and activity by directly binding to the 3′-UTR of CYP3A4 mRNA, may also affect CYP3A4 metabolism and regulation [ 121 ].…”