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.