MECHANISMS OF CHEMICALLY INDUCED PHOTOSENSITIVITY

化学诱导光敏性的机制

• 批准号: 6162233
• 负责人: C F 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/6162233
• 关键词: antibacterial agents; carcinogen testing; hairless mouse; mutagen testing; nonvisual photosensitivity; photosensitizing agents; plasmids; radiation carcinogen; radiation carcinogenesis; singlet oxygen; skin pharmacology; ultraviolet radiation

Summary of Work: Photosensitization can result when 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, or photocarcinogenicity; or it can have beneficial effects as in tumor photodynamic therapy (PDT) and coal tar, anthralin or psoralen (PUVA) therapy for psoriasis. The objective of this research project is to elucidate the photochemical mechanisms whereby photosensitizers exert their toxic or therapeutic effects. Fluoroquinolones (FQ) are a relatively new class of antibacterials that are useful in the treatment of gram-negative bacterial infections. When used in humans FQ's often cause phototoxicity. Recent studies have shown that lomefloxacin and fleroxacin cause squamous cell carcinomas in hairless mice injected with these drugs and irradiated with UV-A (315-400) nm. We have studied the photochemical properties of lomefloxacin and related FQ's to determine why these drugs as a class are phototoxic and why lomefloxacin and fleroxacin are photocarcinogenic. Singlet oxygen (1O2) and superoxide yields for the FQ antimicrobials do not correlate with their phototoxic potentials. However, photocleavage of pBR322 DNA by the FQ antibiotics is at least 10-fold more efficient for difluorinated quinolones (lomefloxcin and fleroxacin) than for monofluorinated analogs. 1O2 does not induce photocleavage. Futhermore, the inhibitory effect of O2 on the induction of frank strand breaks makes it unlikely that superoxide could play a major role in the photocleavage of DNA by these antibiotics. We have now found that upon UVA-irradiation the F-8 fluorine atoms of lomefloxacin and fleroxacin are lost as fluoride with the concomitant generation of a carbene at C-8. In contrast non-photocarcinogenic FLQ's norfloxacin and ciprofloxacin did not exhibit UVA-induced fluoride loss. Oxazepam is a commonly prescribed anti-anxiety drug that has been shown to induce hepatocellular adenomas and carcinomas in mice. Studies conducted by the National Toxicology Program have shown that mice chronically treated with this drug develop cataracts. We have found that while the drug itself is a poor generator of singlet oxygen, one of its metabolites, 6-chloro-4-phenyl-2(1H)-quinazoline, is able to sensitize the formation of 1O2 with high efficiency. Finally, 5,7,9(11),22- ergosta-tetraen-3 -ol and 5,7,9(11)-cholestatrien-3-ol have been identified as potential chromophores responsible the bioeffects of UVA in the skin.

工作总结：当光与光相互作用时会产生光敏化。 皮肤和眼睛中的内源性或外源性化学试剂。 这 过程可能会产生不良的临床后果，例如 光毒性（过度晒伤）、光过敏或 光致癌性；或者它可以像在肿瘤中一样产生有益的作用 光动力疗法 (PDT) 和煤焦油、蒽林或补骨脂素 (PUVA) 治疗牛皮癣。 该研究项目的目标是 阐明光敏剂发挥作用的光化学机制 它们的毒性或治疗作用。氟喹诺酮类药物（FQ）是一种 相对较新的一类可用于治疗的抗菌药物 革兰氏阴性细菌感染。 当FQ经常用于人类时 引起光毒性。最近的研究表明，洛美沙星和 注射氟罗沙星的无毛小鼠可引起鳞状细胞癌 这些药物并用 UV-A (315-400) nm 照射。 我们研究了 洛美沙星的光化学性质及相关 FQ 的测定 为什么这些药物作为一类具有光毒性以及为什么洛美沙星和 氟罗沙星具有光致癌性。单线态氧 (1O2) 和超氧化物 FQ 抗菌剂的产量与其光毒性不相关 潜力。 然而，FQ 抗生素对 pBR322 DNA 的光裂解 二氟喹诺酮类药物的效率至少提高 10 倍 （洛美沙星和氟罗沙星）优于单氟化类似物。 1O2 确实 不引起光裂解。 此外，O2 对 弗兰克链断裂的诱导使得超氧化物不太可能 可能在这些抗生素对 DNA 的光裂解中发挥重要作用。 我们现在发现，在 UVA 照射下，F-8 氟原子 洛美沙星和氟罗沙星随伴随物以氟化物形式损失 在C-8处生成卡宾。 相比之下，非光致癌 FLQ 诺氟沙星和环丙沙星没有表现出 UVA 引起的氟化物损失。 奥沙西泮是一种常用的抗焦虑药物，已被证明 诱导小鼠肝细胞腺瘤和肝细胞癌。研究 国家毒理学计划进行的研究表明，小鼠 长期使用这种药物治疗会出现白内障。 我们发现 虽然药物本身不能产生单线态氧，但其之一 代谢物 6-氯-4-苯基-2(1H)-喹唑啉，能够致敏 1O2的形成效率很高。 最后，5,7,9(11),22- ergosta-tetraen-3-ol 和 5,7,9(11)-cholestatrien-3-ol 已被 被确定为负责 UVA 生物效应的潜在发色团 皮肤。