Imai Hirotaka
School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan.
Yakugaku Zasshi. 2004 Dec;124(12):937-57. doi: 10.1248/yakushi.124.937.
Excessive production of reactive oxygen species (ROS) may lead to oxidative stress, loss of cell function, and cell death by apoptosis or necrosis. Recently, ROS have gained attention as important second messengers. ROS lifetimes can be very short, and many types of ROS cannot penetrate organelle membranes. It is therefore thought that only ROS signal molecules that are generated locally in an organelle are transduced when cells are stimulated. Lipid hydroperoxides are one type of ROS of which the biological function has not yet been clarified. The phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) is a unique antioxidant enzyme and separately distributed to the mitochondria, nucleus, nucleoli, and cytosol, where it regulates phospholipid hydroperoxide and fatty acid hydroperoxide as signal molecules. This review focuses on the structure and biological functions of PHGPx in mammalian cells. Overexpression of different types of PHGPx in the RBL2H3 cell line provides a useful model system with which to clarify the ability of different types of PHGPx to modulate cellular function and the importance of lipid hydroperoxides as signal molecules. Transformant studies show that lipid hydroperoxide is an activator of lipoxygenase and cyclooxygenase and participates in inflammation, cardiolipin hydroperoxide is the signal molecule for the release of cytochrome c during apoptotic cell death, and PHGPx is a signal regulator in the IgE receptor-mediated signaling pathway. It is becoming clear that PHGPx has an important role in spermatogenesis, sperm function, and embryonic development, and its deficiency is implicated in human infertility and in embryonic lethality of PHGPx knockout mice.
活性氧（ROS）的过度产生可能导致氧化应激、细胞功能丧失以及细胞通过凋亡或坏死死亡。最近，ROS作为重要的第二信使受到了关注。ROS的寿命可能非常短，并且许多类型的ROS无法穿透细胞器膜。因此，人们认为当细胞受到刺激时，只有在细胞器中局部产生的ROS信号分子才会被转导。脂质氢过氧化物是一类生物学功能尚未明确的ROS。磷脂氢过氧化物谷胱甘肽过氧化物酶（PHGPx，GPx4）是一种独特的抗氧化酶，分别分布于线粒体、细胞核、核仁和细胞质中，在这些部位它将磷脂氢过氧化物和脂肪酸氢过氧化物作为信号分子进行调节。本综述聚焦于哺乳动物细胞中PHGPx的结构和生物学功能。在RBL2H3细胞系中过表达不同类型的PHGPx提供了一个有用的模型系统，用以阐明不同类型的PHGPx调节细胞功能的能力以及脂质氢过氧化物作为信号分子的重要性。转化体研究表明，脂质氢过氧化物是脂氧合酶和环氧化酶的激活剂，参与炎症反应，心磷脂氢过氧化物是凋亡细胞死亡过程中细胞色素c释放的信号分子，并且PHGPx是IgE受体介导的信号通路中的信号调节剂。越来越清楚的是，PHGPx在精子发生、精子功能和胚胎发育中具有重要作用，其缺乏与人类不育以及PHGPx基因敲除小鼠的胚胎致死有关。
