Understanding Pharmaco-Epigenomic Response of Antipsychotic Drugs Using Genome-Wide MicroRNA Expression Profile in Liver Cell Line

Abstract

Interindividual variability in drug response is a major concern among patients undergoing antipsychotic drug treatment. Apart from genetic and physiological factors, this variability in drug response could also be attributed to epigenetic mechanisms. The microRNAs (miRNAs) are key epigenetic markers that play an important role in pathogenesis and drug response. Several studies have shown that miRNAs are implicated in regulating the expression of various genes involved in drug metabolism and transport. In a conventional clinical setup, it is extremely difficult to distinguish the role of miRNA in pathogenesis and drug response as it is difficult to obtain drug naïve patients. To resolve this issue, we aimed to identify the role of antipsychotic drug treatment in inducing miRNA expression under an in vitro condition using a hepatic cell line. A liver cell line was treated with a maximum tolerable drug dosage model for haloperidol, clozapine in monotherapy, and their combination in polytherapy. Genome-wide miRNA profiling was performed using 60,000 miRNA probes in the microarray format in different treatment groups. Several miRNAs were observed to be differentially expressed impacting the pharmacokinetic, pharmacodynamics, and epigenomics properties of antipsychotic drug treatment. Interestingly, some of these miRNA expression patterns were similar to reported miRNA observations on schizophrenia pathogenesis. This study unravels the potential role of miRNAs in the mechanism of action of the antipsychotic drug and could also reflect in drug-induced side effects. This study also signifies the importance of pharmacoepigenomics approach while evaluating the role of miRNAs in pathogenesis.