MicroRNAs 103 and 107 regulate the expression of Human Cytochrome P450 2C8

Abstract

CYP2C8, which is a highly inducible member of the CYP2C family is involved in the metabolism of therapeutics and endogenous compounds. CYP2C8 is regulated by a variety of nuclear receptors such as GR, CAR and HNF4α. The expression of CYP2C8 has been consistently observed to be low in tumor cell lines. We hypothesized that miRNAs might be involved in the regulation of CYP2C8. Microarray analysis showed several miRNA to be upregulated in HepG2 cell line. A potential recognition element was identified in the 3′ untranslated region of CYP2C8, which matches with miR 103 and miR 107. We investigated if these are involved in CYP2C8 expression. Reporter assays in human hepatocytes with miRNAs revealed that both could identify the recognition element in the 3′ UTR of CYP2C8 mRNA. We found that overexpression of miRNAs in human primary hepatocytes decreases the transactivation of luciferase reporter, whereas the luciferase activities are increased by inhibition of miRNAs. CYP2C8 protein expression in human primary hepatocytes is decreased by overexpression of miRNAs. Conversely, inhibition of miRNAs results in an increase of CYP2C8 protein level. However, neither overexpression nor inhibition of miRNAs affect s the CYP2C8 mRNA levels. We conclude that miR103 and 107 post‐transcriptionally regulate human CYP2C8. The increased expression of miRNAs might be a responsible for low expression of CYP2C8 protein in HepG2 cells.