Post-transcriptional regulation of human pregnane X receptor by micro-RNA affects the expression of cytochrome P450 3A4.
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.
Takagi
Shingo
S
Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Nakajima
Miki
M
Mohri
Takuya
T
Yokoi
Tsuyoshi
T
D020413:3' Untranslated Regions / Q000235:genetics / Q000378:metabolism*; D018938:Caco-2 Cells; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000201:enzymology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D000077297:Pregnane X Receptor; D014176:Protein Biosynthesis / Q000502:physiology*; D011987:Receptors, Steroid / Q000096:biosynthesis* / Q000235:genetics
D020413:3' Untranslated Regions; D035683:MicroRNAs; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human