Formation and Detoxification of Lipid Hydroperoxides in Photosensitized Cells

以脂质过氧化形式的膜损伤可能介导许多光活化染料和颜料(光动力增感剂)的细胞毒性效应。不饱和磷脂和胆固醇敏化光氧化产生的脂氢过氧化物(LOOHs)对膜的结构和功能有许多不利影响。光过氧化的许多方面在分子和细胞水平上仍然知之甚少，包括：(A)不同脂类的相对反应性及其调节方式；(B)酶解毒反应，特别是涉及硒和谷胱甘肽的反应。在过去膜光氧化经验的基础上，该项目将以全面的方式解决每个问题，从模型系统(脂膜、红细胞膜)的研究进展到细胞领域(培养的白血病和内皮细胞)。将使用各种与生物相关的增敏剂(卟啉、酞菁)和最先进的分析技术(克隆生存分析、放射化学和电化学检测的高效液相色谱)。考虑到(A)利用光动力效应的实用新方法(例如光疗法)的迅速发展，以及(B)环境毒性的风险日益增加，这些研究是及时和相关的。

Membrane damage in the form of lipid peroxidation may mediate the cytotoxic effects of many photoactivatable dyes and pigments (photodynamic sensitizers). Lipid hydroperoxides (LOOHs) generated by sensitized photooxidation of unsaturated phospholipids and cholesterol have numerous adverse effects on membrane structure and function. Many aspects of photoperoxidation are still poorly understood at the molecular and cellular level, including (a) relative reactivity of different lipid classes and how this is modulated; and (b) enzymatic detoxification reactions, specifically those involving selenium and glutathione. Building on past experience in membrane photooxidation, this project will address each of these questions in comprehensive fashion, progressing form studies on model systems (liposomal membranes, erythrocyte ghosts) to the cellular domain (cultured leukemia and endothelial cells). A variety of biologically relevant sensitizers (porphyrins, phthalocyanines) and state-of-the-art analytical techniques (clonogenic survival assays, liquid chromatography with radiochemical and electrochemical detection) will be used. These studies are timely and relevant in view of (a) the rapid development of practical new approaches that exploit photodynamic effects (e.g. phototherapies), and (b) the growing risks of environmental toxicity.//