Flutamide-induced cytotoxicity and oxidative stress in an in vitro rat hepatocyte system.
Flutamide-induced cytotoxicity and oxidative stress in an in vitro rat hepatocyte system.
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DOI：
10.1155/2014/398285
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发表时间：
2014
影响因子：
--
通讯作者：
O'Brien P
中科院分区：
文献类型：
--
作者：
Al Maruf A;O'Brien P
氟替卡松（FLU）是一种雄激素受体的竞争性拮抗剂，已报告在某些患者中诱导严重的肝损伤。几个实验模型表明，药物治疗期间的炎症发作使动物易于组织损伤。本研究利用体外氧化应激炎症系统研究了FLU对大鼠肝细胞的分子毒性机制。当在加入FLU之前向肝细胞中加入具有过氧化物酶或铁（II）[Fe（II）]（部分模拟体内炎症）的无毒过氧化氢（H2 O2）生成系统（葡萄糖/葡萄糖氧化酶）时，观察到FLU诱导的细胞毒性和脂质过氧化（LPO）增加，分别被6-N-丙基-2-硫氧嘧啶或去铁胺降低。N-乙酰半胱氨酸在此系统中降低FU诱导的细胞毒性。有效的抗氧化剂，例如Trolox（（±）-6-羟基-2，5，7，8-四甲基苯并二氢吡喃-2-羧酸）、白藜芦醇（3，5，4 ′-三羟基-反式-芪）和DPPD（N，N′-二苯基-1，4-苯二胺）也显著降低了FLU-induced细胞毒性和LPO，并增加了过氧化物酶H2 O2生成系统中线粒体膜电位（MMP）和谷胱甘肽（GSH）水平。TEMPOL（4-羟基-2，2，6，6-四甲基哌啶-1-氧基），一种已知的活性氧（ROS）清除剂和超氧化物歧化酶模拟物，也显着降低FLU在该系统中引起的毒性。这些结果提高了炎症的存在或不存在可能是药物诱导的肝毒性的另一个易感因素的可能性。
Flutamide (FLU) is a competitive antagonist of the androgen receptor which has been reported to induce severe liver injury in some patients. Several experimental models suggested that an episode of inflammation during drug treatment predisposes animals to tissue injury. The molecular cytotoxic mechanisms of FLU in isolated rat hepatocytes using an in vitro oxidative stress inflammation system were investigated in this study. When a nontoxic hydrogen peroxide (H2O2) generating system (glucose/glucose oxidase) with peroxidase or iron(II) [Fe(II)] (to partly simulate in vivo inflammation) was added to the hepatocytes prior to the addition of FLU, increases in FLU-induced cytotoxicity and lipid peroxidation (LPO) were observed that were decreased by 6-N-propyl-2-thiouracil or deferoxamine, respectively. N-Acetylcysteine decreased FLU-induced cytotoxicity in this system. Potent antioxidants, for example, Trolox ((±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), resveratrol (3,5,4′-trihydroxy-trans-stilbene), and DPPD (N,N′-diphenyl-1,4-phenylenediamine) also significantly decreased FLU-induced cytotoxicity and LPO and increased mitochondrial membrane potential (MMP) and glutathione (GSH) levels in the H2O2 generating system with peroxidase. TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl), a known reactive oxygen species (ROS) scavenger and superoxide dismutase mimetic, also significantly decreased toxicity caused by FLU in this system. These results raise the possibility that the presence or absence of inflammation may be another susceptibility factor for drug-induced hepatotoxicity.
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影响因子：
3.8
作者：
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