University of Ljubljana, Faculty of Medicine, Institute of Pathophysiology, Zaloska 4, SI-1000 Ljubljana, Slovenia.
Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier, 4, 28029 Madrid, Spain.
Int J Mol Sci. 2022 Jul 27;23(15):8292. doi: 10.3390/ijms23158292.
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 HO-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 HO, 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.
根据 Roussel Uclaf 因果关系评估方法，用于治疗精神分裂症的抗精神病药物可导致药物性肝损伤 (DILI)。在这些 DILI 病例中，氧化应激在引发损伤中的作用尚不清楚。我们反复以实验室警戒水平给予两种第二代抗精神病药物，阿立哌唑和奥氮平，以研究急性氧化应激下应激预防的潜在机制。这些药物连续给药长达 8 周。为此，使用适合代谢研究的肝癌 Fao 细胞，因为原代肝细胞在培养中仅存活约 1 周。通过抗氧化酶活性测定、基因表达和蛋白质定量，在 HO 处理的细胞中研究了四种应激反应 - 氧化应激反应、DNA 损伤反应以及内质网和线粒体中的未折叠蛋白反应。在阿立哌唑处理的细胞中，氧化剂条件增加了抗氧化酶的活性，并上调了与氧化应激反应相关的基因和蛋白质。虽然与 DNA 损伤反应相关的基因，Gadd45 和 p21，在阿立哌唑和奥氮平处理的细胞中均上调，但只有阿立哌唑处理与 HO 反应的上调相关，这也与更好的生存相关。内质网应激诱导的 Chop 也上调；然而，内质网或线粒体未折叠蛋白反应均未被激活。我们得出结论，只有阿立哌唑，而不是奥氮平，可保护肝细胞免受氧化应激。这一发现可能与具有高氧化应激风险生活方式的精神分裂症患者有关，需要在体内进行验证。
