Abstract

ObjectiveTo determine the mechanism of hepatic drug metabolizing enzyme down‐regulation in chronic kidney disease (CKD).MethodsHepatic CYP3A1, CYP3A2 and CYP2C11 mRNA expression were determined in rats with surgically induced CKD. Chromatin Immunoprecipitation (ChIP) was performed to determine nuclear receptor and epigenetic mediated differences in the promoter region of these enzymes.ResultsHepatic CYP3A and CYP2C11 mRNA expression was significantly decreased in CKD rats compared to controls (P<0.05). RNA polymerase II binding to the CYP3A and CYP2C11 promoter regions was decreased in CKD rats (P<0.05). ChIP also revealed a decreased PXR binding to the CYP3A2 promoter in CKD rats (P<0.05). HNF4α binding to the CYP3A and CYP2C11 promoter regions was also decreased compared to controls (P<0.05). The decrease in PXR and HNF4α binding was concurrent with diminished histone 4 acetylation in the CYP3A2 promoter locus for nuclear receptor activation.ConclusionsWe demonstrate a novel mechanism of drug metabolizing enzyme regulation in CKD. Our results show that decreased CYP3A and CYP2C11 mRNA expression is secondary to decreased PXR and HNF4α binding as a result of histone modulation in CKD. This research is supported by the Natural Sciences and Engineering Research Council.

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