Mitochondrial respiration is uniquely associated with the prooxidant and apoptotic effects of N-(4-hydroxyphenyl)retinamide
Mitochondrial respiration is uniquely associated with the prooxidant and apoptotic effects of N-(4-hydroxyphenyl)retinamide
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DOI：
10.1074/jbc.m106559200
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发表时间：
2001-12-07
影响因子：
4.8
通讯作者：
Lotan, R
中科院分区：
文献类型：
--
作者：
Hail, N;Lotan, R
合成类维甲酸N-（4-羟基苯基）维甲酸（4HPR）正在化学预防和治疗临床试验中进行研究。然而，其作用机制仍未完全阐明。在先前的研究中，线粒体活性氧的增加被认为是4HPR发挥其促凋亡作用的机制之一。本研究利用人类皮肤鳞状细胞癌细胞和呼吸缺陷克隆，探讨线粒体呼吸是否需要4HPR作用。在亲本细胞中，4HPR迅速促进过氧化氢的产生，随后是线粒体通透性转变、半胱天蛋白酶活性和DNA断裂。短期暴露于4HPR也抑制亲本细胞的耗氧量。这种活性被抗氧化剂维生素C逆转，表明4HPR的促进氧化作用直接损害了线粒体功能。在呼吸缺陷克隆中，4HPR的促凋亡特性明显减弱，说明线粒体呼吸在4HPR诱导的细胞死亡中起着核心作用。在亲代细胞中，研究人员检测了各种线粒体抑制剂，以确定与4HPR促氧化活性相关的潜在位点。配合物II的抑制剂和配合物III的中心i抑制剂增强了4hpr诱导的过氧化氢生成。配合物I抑制剂、配合物III的中心o抑制剂、氰化物、寡霉素A和辅酶Q类似物降低了4hpr诱导的过氧化氢生成。辅酶Q类似物在这方面非常有效，并且它们也阻断了中心i抑制剂与4HPR联合时过氧化氢产生的增强。这些结果表明，4HPR的抗氧化特性与通过在复合物I和/或复合物III的o中心的醌结合位点发生的酶促氧化还原代谢有关。
The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) is being examined in both chemoprevention and therapy clinical trials. Yet, its mechanism(s) of action is still not fully elucidated. In previous studies, an increase in mitochondrial reactive oxygen species has been proposed as one mechanism through which 4HPR could exert its proapoptotic effects. This study explored whether mitochondrial respiration is required for 4HPR action using human cutaneous squamous cell carcinoma cells and respiration-deficient clones. In parental cells, 4HPR rapidly promoted hydroperoxide production followed by mitochondrial permeability transition, caspase activity, and DNA fragmentation. Short term exposure to 4HPR also inhibited oxygen consumption in parental cells. This activity was reversed by the antioxidant vitamin C indicating the prooxidant effect of 4HPR directly impaired mitochondrial function. In respiration-deficient clones, the proapoptotic qualities of 4HPR were conspicuously diminished illustrating a central role for mitochondrial respiration in 4HPR-induced cell death. In parental cells, various mitochondrial inhibitors were examined to determine potential sites associated with the prooxidant activity of 4HPR. Inhibitors of Complex II as well as center i inhibitors of Complex III enhanced 4HPR-induced hydroperoxide production. Complex I inhibitors, center o inhibitors of Complex III, cyanide, oligomycin A, and coenzyme Q analogues decreased 4HPR-induced hydroperoxide production. The coenzyme Q analogues were very effective in this respect, and they also blocked the enhanced by droperoxide production obtained when center i inhibitors were combined with 4HPR. These results suggest the prooxidant property of 4HPR is associated with redox metabolism via an enzymatic process occurring at a quinone-binding site in Complex I and/or center o of Complex III.