MECHANISMS OF CHEMICALLY INDUCED PHOTOSENSITIVITY

当光与内源性或外源性的光相互作用时， 皮肤和眼睛中的外源性化学物质。 这个过程可以产生 不良临床后果，如光毒性（夸大 晒伤）、光过敏或光致癌性;或者它可能具有 如在肿瘤光动力疗法（PDT）和煤焦油中的有益效果， 蒽林或补骨脂素（PUVA）治疗银屑病。 的目标 本研究计划旨在阐明光化学机制， 由此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， 可用于治疗革兰氏阴性细菌感染。 使用时 在人类中，FQ'经常引起光毒性。最近的研究表明 洛美沙星导致无毛小鼠鳞状细胞癌 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， 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 是光致癌的单线态氧（1 O2）和超氧化物产率为 FQ抗菌剂与其光毒性潜力无关。 然而，FQ抗生素对pBR 322 DNA的光裂解至少是 10-对于二氟喹诺酮类（洛美沙星和 氟罗沙星）比单氟化类似物更好。 1 O2不诱导 光裂解 Fuxyline，O2对诱导的抑制作用 坦率的链断裂使得超氧化物不太可能发挥作用， 在这些抗生素对DNA的光裂解中起主要作用。 光裂解可能是由于自由基机制， 从糖-磷酸骨架上通过- 反式根奥沙西泮是一种常用的抗- 一种焦虑药物，已被证明可诱导 小鼠肝细胞腺瘤和癌。进行的研究 美国国家毒理学计划表明，长期接受 这种药会引起白内障。 我们发现虽然药物本身 是单线态氧的一个差的发电机，它的代谢物之一，6-氯- 4-苯基-2（1H）-喹唑啉，能够敏化1 O2的形成 具有高效率。

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.