MECHANISMS OF CHEMICALLY INDUCED PHOTOSENSITIVITY

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物质。这 这一过程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；或者它可以像对肿瘤一样具有有益的作用 光动力疗法(PDT)和煤焦油、蒽啉或补骨脂素(PUVA) 治疗牛皮癣。这项研究项目的目的是 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(FQ)是一种 在治疗中有用的相对较新的一类抗菌药 革兰氏阴性细菌感染。当用于人类时，FQ经常 会造成光毒性。最近的研究表明，洛美沙星和 氟罗沙星致无毛小鼠鳞状细胞癌 用UV-A(315-400)nm照射。我们已经研究了 洛美沙星的光化学性质及相关荧光定量测定 为什么这些药物作为一个类别是光毒性的，为什么洛美沙星和 氟罗沙星是光致癌物质。单线态氧(1O2)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pBR322 DNA的光切作用 对二氟喹诺酮类药物的效率至少高出10倍 (洛美沙星和氟罗沙星)优于单氟类似物。1O2可以。 不会引起光分裂。此外，O2对植物生长发育的抑制作用 直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的光解中起主要作用。 我们现在已经发现，在UVA照射下，F-8氟原子 洛美沙星和氟罗沙星以氟化物的形式丢失 在C-8生成卡宾。与之形成对比的是非致光性的FLQ 诺氟沙星和环丙沙星未表现出UVA引起的氟丢失。 奥沙西潘是一种已被证明的常用抗焦虑药物 诱发小鼠肝细胞腺瘤和肝癌。研究 由国家毒理学项目进行的研究表明，老鼠 长期使用这种药物治疗会患上白内障。我们发现， 虽然这种药物本身不太能产生单线态氧，但它的一个 代谢物6-氯-4-苯基-2(1H)-喹唑啉能够增敏 高效率地形成1O2。最后，5，7，9(11)，22- 麦角四烯-3-醇和5，7，9(11)-胆三烯-3-醇 长波紫外线生物效应的潜在发色团研究 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.