Epigenetic modifications in drug-induced liver injury: A systematic review

Abstract

Genetic susceptibility has been identified in idiosyncratic drug-induced liver injury, a potentially severe adverse reaction towards drugs, herbal products and dietary supplements. However, its occurrence cannot be fully explained by the presence of genetic variants in specific genes, suggesting that other factors are involved. Drug-induced liver injury epigenetic signatures could help explain genetic regulatory mechanisms behind this disease and might provide disease biomarkers. This systematic review aims to analyse all available information on epigenetic risk association studies in drug-induced liver injury. The main inclusion criterion was population studies on idiosyncratic drug-induced liver injury with significant risk association analysis between drug-induced liver injury and an epigenetic regulation mechanism. Out of the 7 included articles, 6 focused on DNA methylation and 1 on long noncoding RNA. All of the studies were on antituberculosis drug-induced liver injury and came from Asia. CpG site methylation in the CYP2D6 (odds ratio: 9.19, 95% confidence interval: 3.26-25.89, P < .001) and NAT2 (odds ratio: 8.37, 95% confidence interval: 2.39-29.32, P = .001) promoters conferred the highest risk. Hypomethylation of LINE-1 and Alu transposable elements has potential as antituberculosis drug-induced liver injury biomarkers, showing an area under the curve value of 0.94. To conclude, the studies mainly focused on DNA methylation modifications associated with antituberculosis drug-induced liver injury, with all of them coming from Asia, where tuberculosis is a public health burden. Despite the lack of knowledge in this area, the evidence has shown that DNA methylation alterations in antituberculosis drug-induced liver injury could have potential as a new diagnostic and therapeutic target.

Keywords: DNA methylation; antituberculosis drug‐induced liver injury; drug‐induced liver injury; epigenetic regulation; hepatotoxicity; idiosyncratic drug‐induced liver injury; liver damage.