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.