MECHANISMS OF CHEMICALLY INDUCED PHOTOSENSITIVITY

工作总结：当光与 皮肤和眼睛中的内源性或外源性化学试剂。 这 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，或 光致癌性;或者它可以有有益的效果，如在肿瘤 光动力疗法（PDT）和煤焦油、蒽林或补骨脂素（PUVA） 牛皮癣的治疗方法 本研究项目的目标是 阐明光敏剂发挥作用的光化学机制 其毒性或治疗效果。氟喹诺酮类（FQ）是一种 相对较新的一类抗菌药物， 革兰氏阴性菌感染的症状 当用于人类时， 引起光毒性。最近的研究表明，洛美沙星和 氟罗沙星在无毛小鼠中引起鳞状细胞癌 用UV-A（315-400）nm照射。 我们研究了 洛美沙星和相关FQ的光化学性质，以确定 为什么这些药物作为一类是光毒性的，为什么洛美沙星和 氟罗沙星具有光致癌性。单线态氧（1 O2）和超氧化物 FQ抗菌剂的产量与其光毒性无关 潜力 然而，FQ抗生素对pBR 322 DNA的光裂解 对二氟喹诺酮类药物至少有效10倍 （洛美沙星和氟罗沙星）比单氟化类似物更好。1 O2是 不诱导光裂解。 Fuketamine，O2对 直接链断裂的诱导使得超氧化物 可能在这些抗生素对DNA的光裂解中发挥重要作用。 我们现在已经发现，在UVA照射下， 洛美沙星和氟罗沙星以氟化物形式损失， 在C-8位生成卡宾。 相反，非光致癌FLQ 诺氟沙星和环丙沙星没有表现出UVA诱导的氟化物损失。 奥沙西泮是一种常用的抗焦虑药物， 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研究表明， 长期服用这种药物会产生白内障。 我们发现 虽然药物本身是单线态氧的不良发生器，但其 代谢产物6-氯-4-苯基-2（1H）-喹唑啉能够致敏 1 O2的生成效率高。 最后，5、7、9（11）、22- 麦角甾-四烯-3-醇和5，7，9（11）-胆甾三烯-3-醇已被 被确定为负责UVA生物效应的潜在发色团， 皮肤

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.