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.

工作摘要：当光与光线相互作用时可能会导致光敏化 皮肤和眼睛中的内源性或外源性化学剂。 这 过程会产生不良的临床后果，例如 光毒性（夸张的晒伤），光照或 光碳促性；否则可能会像肿瘤一样具有有益的作用 光动力疗法（PDT）和煤焦油，Anthralin或psoralen（PUVA） 牛皮癣治疗。 该研究项目的目的是 阐明光敏剂施加的光化学机制 它们的有毒或治疗作用。氟喹诺酮（FQ）是 对治疗有用的相对较新的抗菌类 革兰氏阴性细菌感染。 当人类经常使用时 引起光毒性。最近的研究表明，洛梅沙星和 氟昔蛋白在注射的无毛小鼠中引起鳞状细胞癌 这些药物被UV-A（315-400）NM辐照。 我们研究了 Lomefloxacin及其相关FQ的光化学特性 为什么这些药物为班级是光毒性的，为什么 氟诺霉素是光碳纤维蛋白的。单线氧（1O2）和超氧化物 FQ抗微生物的产量与其光毒性无关 潜力。 但是，通过FQ抗生素对PBR322 DNA的光裂解 对于二氟化奎诺酮，至少高10倍 （Lomefloxcin和fleroxacin）比单荧光的​​类似物。 1o2做 不诱导光电分裂。 futhermore，O2的抑制作用 弗兰克斯特·斯特兰（Frank Strand Breaks）的诱导使超氧化物不太可能 这些抗生素可以在DNA的光电上发挥重要作用。 现在，我们发现在UVA-IRRADITIAD时，F-8氟原子的 lomefloxacin和fleroxans因氟化物而丢失 C-8的碳碳产生。 相比之下 诺福去西星和环丙沙星未表现出UVA诱导的氟化物损失。 奥沙西m是一种普遍处方的抗焦虑药，已显示 在小鼠中诱导肝细胞腺瘤和癌。研究 由国家毒理学计划进行的 长期用这种药物治疗这种白内障。 我们发现 虽然药物本身是单线氧的差发电机，但其中之一 代谢物，6-氯-4-苯基-2（1H） - 喹唑啉，能够敏化 具有高效率的1O2的形成。 最后，5,7,9（11），22- Ergosta-Tetraen-3 -Ol和5,7,9（11）-Cholestatrien-3-Ol是 被确定为负责UVA生物效应的潜在发色团 皮肤。