MECHANISMS OF CHEMICALLY INDUCED PHOTOSENSITIVITY

当光与内源或其他物质相互作用时会产生光敏作用 皮肤和眼睛中的外源性化学物质。这一过程可以产生 不良的临床后果，如光毒性(夸大 晒伤)、光过敏或光致癌；或者它可能有 在肿瘤光动力疗法(PDT)和煤焦油中的有益效果， 安非他林或补骨脂素(PUVA)治疗银屑病。的目标是 本研究旨在阐明其光化学机制。 使这些光敏剂发挥它们的毒性作用。 氟喹诺酮类(FQ)是一类相对较新的抗生素， 用于治疗革兰氏阴性细菌感染。使用时 在人体内，FQ‘经常会引起光毒性。最近的研究表明， 注射洛美沙星引起无毛小鼠鳞状细胞癌 用该药物照射UV-A(315-400)nm。我们已经研究过 洛美沙星的光化学性质及其相关的FQ 确定为什么这些药物作为一类药物具有光毒性以及为什么洛美沙星 是光致癌的。单线态氧(1O2)和超氧化物产额 FQ抗菌剂与其光毒潜力无关。 然而，FQ抗生素对pBR322 DNA的光切作用至少是 二氟喹诺酮类药物的效率提高10倍(洛美沙星和 氟罗沙星)，而不是一氟类似物。吸氧不会导致 光劈裂。此外，O2对诱导的抑制作用 坦率的断链使得超氧化物不太可能起到 在这些抗生素对DNA的光解中起主要作用。 光裂解可能是由自由基机制引起的，包括 氢原子--从糖-磷酸主链上提取 抗生素衍生的自由基。奥沙西潘是一种常用的抗肿瘤药物 一种治疗焦虑的药物，已被证明可导致 小鼠肝细胞腺瘤和癌。进行的研究 国家毒理学计划已经表明，长期使用 这种药物会导致白内障。我们发现，虽然药物本身 不能很好地产生单线态氧，它的代谢物之一6-氯-2 4-苯基-2(1H)-喹唑啉能敏化1O2的形成 而且效率很高。

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 these photosensitizers exert their toxic effects. Fluoroquinolones (FQ) are a relatively new class of antibiotics that are useful in the treatment of gram-negative bacterial infections. When used in humans FQ' often cause phototoxicity. Recent studies have shown that lomefloxacin causes squamous cell carcinomas in hairless mice injected with this drug 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 is 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. Photocleavage might result from a free-radical mechanisms involving hydrogen-atom-abstraction from the sugar-phosphate backbone by an- antibiotic-derived radical. Oxazepam is a commonly prescribed anti- anxiety drug that has been shown to induce the formation of 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.