title: 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.
authors.affiliation: Division of Clinical Pharmacology Department of Laboratory Medicine Karolinska Institutet Karolinska University Hospital, Huddinge SE-141 86 Stockholm Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Ekström
authors.affiliation: Division of Clinical Pharmacology Department of Laboratory Medicine Karolinska Institutet Karolinska University Hospital, Huddinge SE-141 86 Stockholm Sweden.
authors.forename: Ilona
authors.initials: I
authors.lastname: Skilving
authors.affiliation: Division of Clinical Pharmacology Department of Laboratory Medicine Karolinska Institutet Karolinska University Hospital, Huddinge SE-141 86 Stockholm Sweden.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Ovesjö
authors.affiliation: Division of Clinical Pharmacology Department of Laboratory Medicine Karolinska Institutet Karolinska University Hospital, Huddinge SE-141 86 Stockholm Sweden.
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
authors.affiliation: Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Karolinska University Hospital, Huddinge SE-141 86 Stockholm Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Nylén
authors.affiliation: Division of Clinical Pharmacology Department of Laboratory Medicine Karolinska Institutet Karolinska University Hospital, Huddinge SE-141 86 Stockholm Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Rane
authors.affiliation: Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Karolinska University Hospital, Huddinge SE-141 86 Stockholm Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Diczfalusy
authors.affiliation: Division of Clinical Microbiology Department of Laboratory Medicine Karolinska Institutet Karolinska University Hospital, Huddinge SE-141 86 Stockholm Sweden; Palliative Home Care and Hospice Ward ASIH Stockholm Södra Långbro Park Bergtallsvägen 12SE-125 59 Älvsjö Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Björkhem-Bergman
keywords: 4β–hydroxycholesterol; 6β‐hydroxylation of testosterone; CYP3A‐activity; N‐demethylation of dextromethorphan; PPARα; VDR; cytochrome P450 3A4; drug metabolism; miR‐27b; microRNA; vitamin D