Fluoroquinolone antimicrobials:: Singlet oxygen, superoxide and phototoxicity
Fluoroquinolone antimicrobials:: Singlet oxygen, superoxide and phototoxicity
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DOI：
10.1111/j.1751-1097.1998.tb05217.x
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发表时间：
1998-04-01
影响因子：
3.3
通讯作者：
Chignell, CF
中科院分区：
文献类型：
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作者：
Martínez, LJ;Sik, RH;Chignell, CF
氟喹诺酮类抗菌药物具有光敏性，在人和动物中均引起光毒性反应。在人体中报道的光毒性顺序为：氟罗沙星>洛美沙星、培氟沙星>环丙沙星>依诺沙星、诺氟沙星和氧氟沙星。体内和体外研究均将这种光毒性与活性氧（包括过氧化氢和羟基自由基）的产生相关。我们通过检测几种氟喹诺酮、萘啶和其他结构相关化合物在1270 nm处的单线态氧（O-1（2））发光来确定单线态氧产生的量子产率（Phi（Delta））。在pD7.5的磷酸盐缓冲液中，所有氟喹诺酮类药物的Phi（Delta）值都很低，范围在0.06 - 0.09之间。我们还测定了这些化合物的O-1（2）猝灭常数，除洛美沙星的速率常数为1.8 × 10（7）M-1 s（-1）外，它们的O-1（2）猝灭常数均在10（6）M-1 s（-1）量级。Phi（Delta）值在极性较低的溶剂如甲醇中显著降低（0.007小于或等于Phi（Delta）小于或等于0.02），这些抗生素产生的O-1（2）与报道的光毒性顺序无关，我们还使用电子顺磁共振和自旋陷阱5，5-二甲基-1-吡咯啉N-氧化物测量了这些抗菌剂在二甲基亚砜中的超氧化物的光生（λ> 300 mm）。虽然氟喹诺酮类药物的超氧化物生成相对速率与光毒性等级之间不存在一一对应关系，但光毒性越强的化合物往往以更快的速率生成超氧化物。然而，观察到的差异幅度似乎不足以解释一般人和动物受试者中氟喹诺酮光毒性效力的范围，特别是氟罗沙星和洛美沙星的高活性。对于后一种药物，F-8原子作为氟化物的光诱导损失和伴随的C-8高度反应性卡宾的产生为其有效的光毒性和光致癌特性提供了更合理的机制。
The fluoroquinolone antibacterial agents possess photosensitizing properties that lead to phototoxic responses in both human and animal subjects, The phototoxicity order reported in humans is: fleroxacin > lomefloxacin, pefloxacin >> ciprofloxacin > enoxacin, norfloxacin and ofloxacin, Studies both in vivo and in vitro have related this phototoxicity to the generation of reactive oxygen species including hydrogen peroxide and the hydroxyl radical. We determined the quantum yields of singlet oxygen generation (Phi(Delta)) by detection of the singlet oxygen (O-1(2)) luminescence at 1270 mn for several fluoroquinolones, naphthyridines and other structurally related compounds. All the fluoroquinolones examined have low Phi(Delta) values ranging from 0.06 to 0.09 in phosphate buffer at pD 7.5, We also determined the O-1(2) quenching constants for these compounds and their values were on the order of 10(6) M-1 s(-1), except for lomefloxacin whose rate constant was 1.8 x 10(7) M-1 s(-1). The Phi(Delta) values were significantly decreased in a solvent of lower polarity such as methanol (0.007 less than or equal to Phi(Delta) less than or equal to 0.02), The production of O-1(2) by these antibiotics did not correlate with the order reported for their phototoxicity, We also measured the photogeneration (lambda > 300 mm) of superoxide by these antibacterials in dimethylsulfoxide using electron paramagnetic resonance and the spin trap 5,5-dimethyl-1-pyrroline N-oxide. Although there is not a one-to-one correspondence between the relative rates of superoxide generation and the phototoxicity ranking of the fluoroquinolones, the more phototoxic compounds tended to produce superoxide at a faster rate. Nevertheless, the magnitudes of the observed differences do not appear sufficient to explain the range of fluoroquinolone phototoxicity potencies in human and animal subjects in general and the high activity of fleroxacin and lomefloxacin in particular. For these latter drugs the photoinduced loss of the F-8 atom as fluoride and the concomitant generation of a highly reactive carbene at C-8 provide a more plausible mechanism for their potent phototoxic and photocarcinogenic properties.