Otreba Michał, Wrześniok Dorota, Beberok Artur, Rok Jakub, Buszman Ewa
Acta Pol Pharm. 2016 Jul;73(4):903-911.
Fluphenazine and perphenazine as a phenothiazine-class antipsychotic drugs are widely used to treat psychoses and schizophrenia, however their use is associated with significant side effects such as extrapyramidal symptoms as well as ocular and skin disorders. The aim of this study was to examine the effect of fluphenazine and perphenazine on cell viability, melanogenesis and antioxidant defense system in normal human melanocytes. It has been shown that both phenothiazines induce concentration-dependent loss in cell viability. The value of EC₅₀. was calculated to be 1.24 and 2.76 μM for fluphenazine and perphenazine, respectively. Fluphenazine in concentration of 1.0 μM and perphenazine in concentrations of 1.0 and 3.0 μM inhibied melanogenesis and decreased microphthalmia-associated transcription factor content. To study the effect of both analyzed drugs on antioxidant defense system in melanocytes, the level of hydrogen peroxide and the activities of antioxidant enzymes: superoxide dismutase, catalase and glutathione peroxidase were determined. Fluphenazine and perphenazine in higher analyzed concentrations caused depletion of melanocytes antioxidant status, what indicated the induction of oxidative stress. The observed changes in melanization process and antioxidant defense system in pigmented cells exposed to fluphenazine and perphenazine in vibo suggest a significant role of melanin and melanocytes in the mechanisms of undesirable side effects of these drugs in vivo, especially directed to pigmented tissues. Moreover, the presented differences in modulation of biochemical processes in melanocytes may be an explanation for various toxic activity of the analyzed phenothiazine derivatives in vivo.
氟奋乃静和奋乃静作为吩噻嗪类抗精神病药物，被广泛用于治疗精神病和精神分裂症，然而它们的使用会带来显著的副作用，如锥体外系症状以及眼部和皮肤疾病。本研究的目的是检测氟奋乃静和奋乃静对正常人黑素细胞的细胞活力、黑素生成和抗氧化防御系统的影响。结果表明，两种吩噻嗪类药物均会导致细胞活力呈浓度依赖性丧失。氟奋乃静和奋乃静的半数有效浓度（EC₅₀）分别计算为1.24 μM和2.76 μM。1.0 μM浓度的氟奋乃静以及1.0 μM和3.0 μM浓度的奋乃静可抑制黑素生成并降低小眼相关转录因子含量。为研究这两种分析药物对黑素细胞抗氧化防御系统的影响，测定了过氧化氢水平以及抗氧化酶超氧化物歧化酶、过氧化氢酶和谷胱甘肽过氧化物酶的活性。较高分析浓度的氟奋乃静和奋乃静导致黑素细胞抗氧化状态耗竭，这表明诱导了氧化应激。在体内暴露于氟奋乃静和奋乃静的色素细胞中观察到的黑素化过程和抗氧化防御系统的变化表明，黑色素和黑素细胞在这些药物体内不良副作用的机制中起重要作用，尤其是针对色素组织。此外，黑素细胞中生化过程调节的差异可能解释了所分析的吩噻嗪衍生物在体内的各种毒性活性。
