The expression, induction and pharmacological activity of CYP1A2 are post-transcriptionally regulated by microRNA hsa-miR-132-5p.

摘要: Cytochrome P450 1A2 (CYP1A2) is one of the most abundant and important drug metabolizing enzymes in human liver. However, little known about post-transcriptional regulation CYP1A2, especially mechanisms involving microRNAs (miRNAs). This study applied a systematic approach to investigate CYP1A2 by miRNAs. Candidate miRNAs targeting 3'-untranslated region (3'-UTR) were screened silico, resulting selection sixty-two potential for further analysis. The levels two miRNAs, hsa-miR-132-5p hsa-miR-221-5p, inversely correlated with expression mRNA transcripts normal liver tissue samples represented Cancer Genome Atlas (TCGA) dataset. interactions between these cognate sequences evaluated using luciferase reporter gene studies electrophoretic mobility shift assays, which direct interaction was confirmed binding site present 3'-UTR. Experiments or random miRNA controls introduced into HepG2, Huh-7 HepaRG hepatic cell lines showed that only suppressed endogenous lansoprazole-induced at biological activity, protein production, transcript levels. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH) assays attenuates CYP1A2-mediated, lansoprazole-enhanced, flutamide-induced toxicity. Results from multilayer experiments demonstrate suppresses this suppression able decrease extent an adverse drug-drug lansoprazole flutamide.