miRNA‐27b levels are associated with CYP3A activity in vitro and in vivo

Abstract

Previous in vitro studies have shown that microRNA‐27b (miR‐27b) may regulate mRNA levels of CYP3A4, vitamin D receptor (VDR), and Peroxisome proliferator‐activated receptor α (PPAR α) as well as CYP3A4 protein expression and activity. In vitro studies have also shown that vitamin D may affect the expression of CYP3A4. The primary aim of this pilot study was to investigate the association between miR‐27b and CYP3A expression and activity. The secondary aim was to investigate the association between 25‐hydroxy vitamin D in serum and CYP3A activity. Mi‐RNA‐27b was quantified using real‐time PCR in serum samples (n = 28) and 25‐hydroxyvitamin D was measured and correlated with the levels of the endogenous CYP3A activity marker 4β‐hydroxycholesterol. In addition, the correlation between miR‐27b and CYP3A activity, measured by dextromethorphan N‐demethylation and 6β‐hydroxylation of testosterone and the gene expression of CYP3A4, VDR and PPAR α were assessed in 20 human liver samples. A significant association between circulatory miR‐27b levels and 4β‐hydroxycholesterol ratio was found; P = 0.04, and between hepatic miR‐27b levels and CYP3A activity, measured by dextromethorphan N‐demethylation in human liver (P = 0.04). There was no association between hepatic miR‐27b and mRNA levels of CYP3A4, VDR or PPAR α. There was a significant association between serum 25‐hydroxyvitamin D levels and 4β‐hydroxycholesterol ratio, P = 0.002. In conclusion, this pilot‐study supports the hypothesis that miR‐27b levels as well as 25‐hydroxyvitamin D may affect CYP3A activity in vivo. The results indicate that miR‐27b exerts its inhibitory effect on a translational level rather than affecting mRNA levels.

Bioengineered miR-27b-3p and miR-328-3p modulate drug metabolism and disposition via the regulation of target ADME gene expression

“…Previous studies have also demonstrated that miR-27b-3p regulates the expression of CYP3A4 15. , 16. , which is the most abundant hepatic and intestinal drug metabolizing enzyme in humans 17 .…”

“…For instance, miR-27b-3p has been shown to negatively regulate the expression of cytochrome P450s (CYPs) 1B1 in human carcinoma cells13., 14.. Previous studies have also demonstrated that miR-27b-3p regulates the expression of CYP3A415., 16., which is the most abundant hepatic and intestinal drug metabolizing enzyme in humans 17 . Changes in CYP3A4 expression and function will undoubtedly lead to a broader variability in drug metabolism as CYP3A4 contributes to the biotransformation of more than 50% of the drugs used in clinic 18 .…”

Hsa-miR-4277 Decelerates the Metabolism or Clearance of Sorafenib in HCC Cells and Enhances the Sensitivity of HCC Cells to Sorafenib by Targeting cyp3a4

“…( 66 ) and Zastrozhin et al. ( 67 ) suggested that the miR-27 family, miR-142, miR-200a, miR-150 or miR-328 could targets to cyp3a4 ( 62 – 67 ). Therefore, our results extended the knowledge of miRNAs on cyp3a4 .…”

Validation of Suitable Reference Genes for Assessing Gene Expression of MicroRNAs in Lonicera japonica

“…miRNA genes are an important class of fine-tuning regulators, playing a major role in a wide range of developmental, biological, and metabolic processes in plants, including metabolism, stress response, vegetative phase changes, organogenesis, and signal transduction ( Mathiyalagan et al, 2013 ). To date, a large number of miRNA families have been described in plants, some of which are directly associated with secondary metabolism synthesis ( Ekström et al, 2015 ). Increasingly, miRNAs have been identified and characterized in some important medicinal herbs ( Song et al, 2009 ; Wu et al, 2012b ) and different tissues of medicinal plants ( Xu et al, 2014 ; Khaldun et al, 2015 ).…”