MiR-155 and other microRNAs downregulate drug metabolizing cytochromes P450 in inflammation

Abstract

In conditions of acute and chronic inflammation hepatic detoxification capacity is severely impaired due to coordinated downregulation of drug metabolizing enzymes and transporters. Using global transcriptome analysis of liver tissue from donors with pathologically elevated C-reactive protein (CRP), we observed comparable extent of positive and negative acute phase response, where the top upregulated gene sets included immune response and defense pathways while downregulation occurred mostly in metabolic and catabolic pathways including many important drug metabolizing enzymes and transporters. We hypothesized that microRNAs (miRNA), which usually act as negative regulators of gene expression, contribute to this process. Microarray and quantitative real-time PCR analyses identified differentially expressed miRNAs in liver tissues from donors with elevated CRP, cholestasis, steatosis, or non-alcoholic steatohepatitis. Using luciferase reporter constructs harboring native and mutated 3′-untranslated gene regions, several predicted miRNA binding sites on RXRα (miR-130b-3p), CYP2C8 (miR-452-5p), CYP2C9 (miR-155-5p), CYP2C19 (miR-155-5p, miR-6807-5p), and CYP3A4 (miR-224-5p) were validated. HepaRG cells transfected with miRNA mimics showed coordinate reductions in mRNA levels and several cytochrome P450 enzyme activities particularly for miR-155-5p, miR-452-5p, and miR-6807-5p, the only miRNA that was deregulated in all four pathological conditions. Furthermore we observed strong negative correlations between liver tissue miRNA levels and hepatic CYP phenotypes. Since miR-155 is well known for its multifunctional roles in immunity, inflammation, and cancer, our data suggest that this and other miRNAs contribute to coordinated downregulation of drug metabolizing enzymes and transporters in inflammatory conditions.