@article {Makiamol.115.100255, author = {Ngome L. Makia and Joyce A. Goldstein}, title = {CYP2C8 is a Novel Target of Peroxisome Proliferator-activated α(PPARα) In Human Liver}, elocation-id = {mol.115.100255}, year = {2015}, doi = {10.1124/mol.115.100255}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Human CYP2C enzymes metabolize ~30\% of clinically prescribed drugs and various environmental chemicals. CYP2C8, an important member of this subfamily, metabolizes the anticancer drug paclitaxel, certain antidiabetic drugs, and endogenous substrates including arachidonic acid to physiologically active epoxyeicosatrienoic acids (EETs). Previous studies from our laboratory showed that microRNA 107 (miR107) and microRNA 103 down-regulate CYP2C8 post-transcriptionally. miR107 is located in intron 5 of the pantothenate kinase 1 (PANK1) gene. p53 has been reported to coregulate the induction of PANK1 and miR107. Here, we examine the possible down regulation of CYP2C8 by drugs capable of inducing miR107. Hypolipidemic drugs such as bezafibrate, known activators of the peroxisome proliferator-activated receptor α (PPARα), induce both the PANK1 gene and miR107 (≈2.5 fold) in primary human hepatocytes. Surprisingly, CYP2C8 mRNA and protein levels were induced by bezafibrate. CYP2C8 promoter activity was increased by ectopic expression of PPARα in HepG2 cells with a further increase after bezafibrate (≈ 18-fold), WY14643 treatment (≈ 10-fold), or the antidiabetic drug rosiglitazone, all known PPAR activators. Promoter sequence analyses, deletion studies, mutagenesis studies and electrophoretic mobility shift assays (EMSAs) identify a PPARα response element (PPRE) located at position -2109 bp relative to the translation start site of CYP2C8. ChIP analysis confirmed recruitment of PPARα to this PPRE after bezafibrate treatment of human hepatocytes. Thus, we show for the first time that CYP2C8 is transcriptionally regulated by PPARα suggesting the potential for drug-drug interactions due to up-regulation of CYP2C8 by PPAR activators.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2015/10/14/mol.115.100255}, eprint = {https://molpharm.aspetjournals.org/content/early/2015/10/14/mol.115.100255.full.pdf}, journal = {Molecular Pharmacology} }