Antipsychotic Drug Aripiprazole Protects Liver Cells from Oxidative Stress

Abstract

Antipsychotics used to treat schizophrenia can cause drug-induced liver injury (DILI), according to the Roussel Uclaf Causality Assessment Method. The role of oxidative stress in triggering injury in these DILI cases is unknown. We repeatedly administrated two second-generation antipsychotics, aripiprazole and olanzapine, at laboratory alert levels to study underlying mechanisms in stress prevention upon acute oxidative stress. The drugs were administered continuously for up to 8 weeks. For this, hepatoma Fao cells, which are suitable for metabolic studies, were used, as the primary hepatocytes survive in the culture only for about 1 week. Four stress responses—the oxidative stress response, the DNA damage response and the unfolded protein responses in the endoplasmic reticulum and mitochondria—were examined in H2O2-treated cells by antioxidant enzyme activity measurements, gene expression and protein quantification. Oxidant conditions increased the activity of antioxidant enzymes and upregulated genes and proteins associated with oxidative stress response in aripiprazole-treated cells. While the genes associated with DNA damage response, Gadd45 and p21, were upregulated in both aripiprazole- and olanzapine-treated cells, only aripiprazole treatment was associated with upregulation in response to even more H2O2, which also coincided with better survival. Endoplasmic reticulum stress-induced Chop was also upregulated; however, neither endoplasmic reticulum nor mitochondrial unfolded protein response was activated. We conclude that only aripiprazole, but not olanzapine, protects liver cells against oxidative stress. This finding could be relevant for schizophrenia patients with high-oxidative-stress-risk lifestyles and needs to be validated in vivo.

Therapeutic Dosage of Antipsychotic Drug Aripiprazole Induces Persistent Mitochondrial Hyperpolarisation, Moderate Oxidative Stress in Liver Cells, and Haemolysis

“…Oxidative stress is an important factor in psychiatric disease development, including schizophrenia [37]. Many antipsychotics can protect against oxidative stress [38][39][40]. Increased survival and higher superoxide dismutase expression under oxidative stress were detected in ARI-and OLA-treated PC12 neuronal model cells compared to the untreated controls [39,41].…”

“…Increased survival and higher superoxide dismutase expression under oxidative stress were detected in ARI-and OLA-treated PC12 neuronal model cells compared to the untreated controls [39,41]. ARI protects liver cells only during oxidative stress by increased activity of antioxidant enzymes and upregulation of proteins associated with oxidative stress response [40] and is bound by glutathione (GSH) [42]. Without an oxidant, ARI does not affect cell death or induce apoptosis, still reducing the rate of hepatocytes' division [9].…”