N-acetylcysteine (NAC), a plant antioxidant naturally found in onion, is a precursor to glutathione. It has been used as a drug since the 1960s and is listed on the World Health Organization (WHO) Model List of Essential Medicines as an antidote in poisonings. There are numerous other uses or proposed uses in medicine that are still in preclinical and clinical investigations. NAC is also used in food supplements and cosmetics. Despite its abundant use, there are projections that the NAC global market will grow in the next five years; therefore, the purpose of this work is to provide a balanced view of further uses of NAC as a dietary supplement. Although NAC is considered a safe substance, the results among clinical trials are sometimes controversial or incomplete, like for many other antioxidants. More clinical trials are underway that will improve our understanding of NAC applicability.

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Effects of aripiprazole on dopamine regulation are being tested as a treatment for patients with a dual diagnosis of schizophrenia and addictions, often cocaine dependence. Aripiprazole has one of the fewest side-effects among the second-generation antipsychotics. Nevertheless, severe aripiprazole hepatotoxicity was reported in persons with a history of cocaine and alcohol abuse. Here we report that therapeutically relevant aripiprazole concentrations, equal to laboratory alert levels in patients’ serum, reduce the rate of hepatocytes’ division. This could be an underlying mechanism of severe liver injury development in the patients with a history of alcohol and cocaine abuse, the two hepatotoxic agents that require increased ability of liver self-regeneration. Monitoring liver functions is, therefore, important in the cases when aripiprazole is co-prescribed or used with drugs with potential hepatotoxic effects.

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.