MECHANISMS OF CHEMICALLY INDUCED PHOTOSENSITIVITY

化学诱导光敏性的机制

• 批准号: 6106701
• 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/6106701
• 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 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 found that the F-8 atoms of lomefloxacin and fleroxacin are photoeliminated as fluoride. Similarly the Cl-8 chlorine atoms of clinafloxacin and Bay y3118 are photoeliminated as chloride. In contrast the non- photocarcinogenic, less phototoxic FLQ's norfloxacin and ciprofloxacin did not exhibit UVA-induced halide loss. We propose that the carbene generated by halide loss is responsible for the photogenotoxicty of the FLQ's. Berberine is an alkaloid from Goldenseal, an herb that is widely used for medical applications including eyewash and skin disinfectant. Goldenseal is currently undergoing testing by the National Toxicology Program. We have found that concentrations of berberine as low as 1uM killed HaCaT keratinocytes when irradiated by UVA. This effect appears to be related to the generation of singlet oxygen and free radicals upon irradiation. The DNA damaging effect of UVA/berberine are being studied using the comet assay. able 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：光敏化可能结果 当光与内源或外源化学剂相互作用时 在皮肤和眼睛中。这个过程可能会产生不良的 当光与内源性相互作用时，可以产生光敏性 或皮肤和眼睛中的外源化学剂。这个过程可以 产生不良的临床后果，例如光毒性 （夸张的晒伤），摄影作用或光碳纤维发明；或它 在肿瘤光动力疗法（PDT）中可能具有有益的作用 以及用于牛皮癣的煤焦油，雌素或牛con（PUVA）疗法。 该研究项目的目的是阐明 光化机制，光敏剂施加了他们的 有毒或治疗作用。氟喹诺酮（FQ）是相对的 新的一类抗菌物，可用于治疗 革兰氏阴性细菌感染。当人类使用时 通常会引起光毒性。最近的研究表明 洛梅沙星和氟沙星引起鳞状细胞癌 无毛小鼠注射了这些药物，并被UV-A辐射 （315-400）NM。我们研究了 lomefloxacin及其相关的FQ s确定为什么这些药物为一种 类是光毒性的，为什么洛梅沙星和氟去星是 光碳纤维促。单线氧（1O2）和超氧化物的产量 FQ抗菌剂与其光毒性无关 潜力。但是，通过FQ对PBR322 DNA的光裂解 抗生素至少对扩散效率提高10倍 喹诺酮类（洛梅氟霉素和氟诺霉素），而不是单荧光的 类似物。 1O2不会诱导光丝分裂。 futhermore， O2对弗兰克链断裂诱导的抑制作用 超级氧化物不太可能在 这些抗生素对DNA的光裂解。我们发现 Lomefloxatin和fleroxat的F-8原子被光启示为 氟化物。同样，钙氟沙星和湾的Cl-8氯原子 Y3118被光照射为氯化物。相比之下 光碳纤维毒素，较少的光毒性FLQ的诺福沙星和 环丙沙星未表现出UVA诱导的卤化物损失。我们建议 卤化物损失产生的卡宾是造成的 FLQ的光生毒素。 berberine是一种生物碱 Goldeneal，一种广泛用于医疗应用的草药 包括眼睛和皮肤消毒剂。 Goldenseal目前是 国家毒理学计划的测试。我们有 发现低至1UM的浓度杀死了HACAT 角质形成细胞被UVA辐照时。这种效果似乎是 与单线氧和自由基的产生有关 辐照。 UVA/berberine的DNA破坏效应正在 使用彗星测定法进行了研究。有能力的临床后果，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，静脉素或牛cor骨 （PUVA）牛皮癣治疗。该研究项目的目的 是为了阐明光化学机制 光敏剂发挥其有毒或治疗作用。 氟喹诺酮（FQ）是一类相对较新的抗菌药物 可用于治疗革兰氏阴性细菌 感染。当人类使用时，FQ通常会引起光毒性。 最近的研究表明，洛梅沙星和氟沙星引起 注入这些药物的无毛小鼠中的鳞状细胞癌 并用UV-A（315-400）nm辐照。我们研究了 洛梅氟沙毒和相关FQ的光化学特性 确定为什么这些药物为类是光毒性的，为什么 lomefloxacin和fleroxacin具有光钙蛋白生成。单线氧 （1O2）和FQ抗微生物的超氧化物产量不得 与它们的光毒性潜力相关。但是，光裂解 通过FQ抗生素的PBR322 DNA至少增加10倍 有效的二氟喹诺酮（Lomefloxcin和Fleroxan）有效 而不是单氟化类似物。 1O2不诱导 光电科。 futhermore，O2对 诱导弗兰克链断裂使超氧化物不太可能 这些可以通过这些在DNA的光丝分裂中发挥重要作用 抗生素。我们现在发现，在UVA-IRRADITIAD时F-8 作为氟化物，洛梅氟沙星的氟原子丧失 随着C-8的碳含量伴随的一代。相比之下 非光芳基FLQ的诺福沙星和环丙沙星没有 表现出UVA诱导的氟化物损失。奥沙西m是一个通常 已证明诱导的规定抗焦虑药 小鼠的肝细胞腺瘤和癌。研究 由国家毒理学计划进行的 用这种药物长期治疗的小鼠会产生白内障。我们有 发现虽然药物本身是单元的差发电机 氧，其代谢物之一， 6-氯-4-苯基-2（1H） - 喹唑啉，能够敏感 具有高效率的1O2形成。最后，5,7,9（11），22- Ergosta-Tetraen-3 -Ol和5,7,9（11）-Cholestatrien-3-Ol是 被确定为负责的潜在发色团 皮肤中的UVA。