High risk of drug toxicity in social isolation stress due to liver dysfunction: Role of oxidative stress and inflammation.

ABSTRACT

BACKGROUND: Previous studies have shown that social isolation stress (SIS) could associate with several systemic diseases; however, the role of SIS on liver dysfunction has yet to be established. This study aimed to investigate the effect of SIS on liver function and possible drug toxicity through liver inflammation and oxidative stress. METHODS: Male Naval Medical Research Institute mice in two groups of SIS and control were treated with typical anti-depressant and anxiolytic agents including fluoxetine, norfluoxetine, desipramine, and imipramine in both groups. Then blood concentrations (or their active metabolites) of these drugs were assessed. Liver function test, including aspartate transaminase (AST), alanine aminotransferase (ALT), total bilirubin, and conjugated bilirubin), oxidative activity, inflammatory cytokines, and the gene expression of cytochrome P450 enzymes were assessed. RESULTS: We observed that the liver enzymes including AST and ALT was slightly higher in SIS animals. The blood concentrations of fluoxetine, norfluoxetine, desipramine, and imipramine were significantly higher in SIS animals. The gene expression of CYP1A2, CYP2A6, CYP2C9, CYP2C29, and CYP2D were significantly decreased in SIS animals. Our results showed that SIS animals had significantly higher level of tumor necrosis factor-α, interleukin-1ß, and interleukin-6. SIS could significantly decrease the activity of antioxidant agent (Glutathione). CONCLUSION: We hypothesized that SIS could induce liver dysfunction and decrease the rate of drug clearance through liver inflammation and oxidative stress; therefore, the blood concentration of anti-depressant/anxiolytic agents should closely monitor in SIS due to the high toxicity of these agents.