Mechanisms Of Chemically Induced Photosensitivity

化学诱导光敏性的机制

• 批准号: 6672981
• 负责人: COLIN CHIGNELL
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6672981
• 关键词: DNA damage; antibacterial agents; carcinogen testing; drug screening /evaluation; environmental exposure; hairless mouse; mutagen testing; photoactivation; photochemistry; photosensitizing agents; radiation carcinogen; radiation carcinogenesis; radiation hazard; radiobiology; singlet oxygen; ultraviolet radiation

Summary of work: Photosensitization can result when UV or visible light interacts with endogenous or exogenous chemical agents in the skin and eyes. This process can produce undesirable clinical consequences, such as phototoxicity (exaggerated sunburn), photoallergy, photocarcinogenicity and/or photomutagenicity ; or it can have beneficial effects as in tumor photodynamic therapy (PDT) and coal tar, anthralin or 8-methoxypsoralen (PUVA) therapy for psoriasis. The objective of this research project is to elucidate the photochemical mechanisms whereby light (UV or visible) in the presence or absence of photosensitizers exerts its toxic effect. We have found that UVA irradiation caused programmed cell death (apoptosis) of skin cells (keratinocytes) 24 hours after exposure as determined by DNA fragmentation electrophoresis and flow cytometry. Juglone, a chemical present in black walnuts, is a component of dietary supplements, hair dyes and walnut oil stains. Crushed black walnut hulls are sometimes applied to the skin to treat fungal, bacterial or viral infections. Juglone is currently undergoing study by the National Toxicology Program. We have found that juglone is toxic to skin cells (keratinocytes), which convert it to highly reactive and toxic free radicals. Ketoprofen, a widely used non-steroidal anti-inflammatory drug (NSAID) that causes both phototoxicity and photoallergy, upon UVA irradiation, induced the formation of protein radicals in methemoglobin, oxyhemoglobin, myoglobin and red blood cells. We have tested the ability of the Tg.AC mouse to detect photocarcinogens (chemicals that cause skin cancer in the presence of light) and found that while this transgenic mouse responds to UV/8-methoxypsoralen, it is not sensitive to UV/lomefloxacin.

工作总结：当紫外线或可见光与皮肤和眼睛中的内源性或外源性化学试剂相互作用时，可能会导致光敏化。该过程可能产生不良的临床后果，例如光毒性（过度晒伤）、光过敏、光致癌性和/或光致突变性；或者它可以像肿瘤光动力疗法 (PDT) 和煤焦油、蒽林或 8-甲氧基补骨脂素 (PUVA) 治疗牛皮癣一样产生有益效果。该研究项目的目的是阐明光化学机制，光（紫外线或可见光）在存在或不存在光敏剂的情况下发挥其毒性作用。通过 DNA 片段电泳和流式细胞术测定，我们发现 UVA 照射在照射后 24 小时会导致皮肤细胞（角质形成细胞）的程序性细胞死亡（细胞凋亡）。胡桃醌是黑核桃中存在的一种化学物质，是膳食补充剂、染发剂和核桃油污剂的成分。有时将压碎的黑胡桃壳涂在皮肤上以治疗真菌、细菌或病毒感染。 Juglone 目前正在接受国家毒理学计划的研究。我们发现胡桃醌对皮肤细胞（角质细胞）有毒，皮肤细胞会将其转化为高反应性和有毒的自由基。酮洛芬是一种广泛使用的非甾体抗炎药 (NSAID)，可引起光毒性和光过敏，在 UVA 照射下，诱导高铁血红蛋白、氧合血红蛋白、肌红蛋白和红细胞中蛋白质自由基的形成。我们测试了 Tg.AC 小鼠检测光致癌物（在光存在下导致皮肤癌的化学物质）的能力，发现虽然这种转基因小鼠对紫外线/8-甲氧基补骨脂素有反应，但它对紫外线/洛美沙星不敏感。