Post-transcriptional Regulation of Human Pregnane X Receptor by Micro-RNA Affects the Expression of Cytochrome P450 3A4

Abstract

Pregnane X receptor (PXR) is a major transcription factor regulating the inducible expression of a variety of transporters and drug-metabolizing enzymes, including CYP3A4 (cytochrome P450 3A4). We first found that the PXR mRNA level was not correlated with the PXR protein level in a panel of 25 human livers, indicating the involvement of post-transcriptional regulation. Notably, a potential miR-148a recognition element was identified in the 3-untranslated region of human PXR mRNA. We investigated whether PXR might be regulated by miR-148a. A reporter assay revealed that miR-148a could recognize the miR-148a recognition element of PXR mRNA. The PXR protein level was decreased by the overexpression of miR-148a, whereas it was increased by inhibition of miR-148a. The miR-148a-dependent decrease of PXR protein attenuated the induction CYP3A4 mRNA. Furthermore, the translational efficiency of PXR (PXR protein/PXR mRNA ratio) was inversely correlated with the expression levels of miR-148a in a panel of 25 human livers, supporting the miR-148a-dependent regulation of PXR in human livers. Eventually, the PXR protein level was significantly correlated with the CYP3A4 mRNA and protein levels. In conclusion, we found that miR-148a post-transcriptionally regulated human PXR, resulting in the modulation of the inducible and/or constitutive levels of CYP3A4 in human liver. This study will provide new insight into the unsolved mechanism of the large interindividual variability of CYP3A4 expression.

Genetic interplay betweenHLA-CandMIR148Ain HIV control and Crohn disease

“…The MIR148A gene is quite polymorphic, however, and variation in the gene region exhibits marked population differentiation representing one of the strongest signatures of selection among 117 miRNA regions tested throughout the genome (14). The levels of miR-148a expression also vary markedly across individuals (15), raising the possibility that genetic variation in the region of MIR148A may affect miR-148a expression, which may in turn affect differential HLA-C expression levels. We sequenced 7.7 kb (−6057 to +1674 relative to the distance from the mature miRNA sequence), including the MIR148A gene and flanking regions in 219 EA, identifying 26 polymorphic positions, of which 11 had a minor allele frequency of ≥5% (Fig.…”

Aryl hydrocarbon receptor nuclear translocator in human liver is regulated by miR-24

“…However, the miRNA:mRNA pairs largely remain to be identified. Recently, we reported that miRNAs were involved in the regulation of human xenobiotics-metabolizing enzymes such as CYP1B1 (Tsuchiya et al, 2006) and CYP2E1 (Mohri et al, 2010) and human nuclear receptors such as pregnane X receptor (Takagi et al, 2008), vitamin D receptor (Mohri et al, 2009), and hepatocyte nuclear factor 4α (Takagi et al, 2010). As a sequel study, we focused on human aryl hydrocarbon receptor nuclear translocator (ARNT).…”

MicroRNAs from biology to future pharmacotherapy: Regulation of cytochrome P450s and nuclear receptors

“…Our data demonstrated that the miR-148a regulates PXR but not CYP3A4 (Takagi et al, 2008). Interestingly, the miR-148-dependent regulation of PXR affected the induction of endogenous CYP3A4 in human colon carcinoma-derived LS180 cells.…”