MiRNA‐27b levels are associated with CYP3A activity in vitro and in vivo. Issue 6 (27th October 2015)

• Record Type: Journal Article
• Authors: Ekström, Lena; Skilving, Ilona; Ovesjö, Marie‐Louise; Aklillu, Eleni; Nylén, Hanna; Rane, Anders; Diczfalusy, Ulf; Björkhem‐Bergman, Linda
• Is Part Of: Pharmacology research & perspectives. Volume 3:Issue 6(2015 Dec)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2015-10-27
• Subjects: 4β–hydroxycholesterol -- 6β‐hydroxylation of testosterone -- CYP3A‐activity -- cytochrome P450 3A4 -- drug metabolism -- microRNA -- miR‐27b -- N‐demethylation of dextromethorphan -- PPAR α -- VDR -- vitamin D; Pharmacology -- Periodicals; Drug development -- Periodicals; 615.105
• DOI: 10.1002/prp2.192
• Languages: English
• ISSNs: 2052-1707

Abstract

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 4 β ‐hydroxycholesterol. In addition, the correlation between miR‐27b and CYP3A activity, measured by dextromethorphan N‐demethylation and 6 β ‐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 4 β ‐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 4 β ‐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.