Spratt T E, Schultz S S, Levy D E, Chen D, Schlüter G, Williams G M
American Health Foundation, Division of Pathology and Toxicology, 1 Dana Road, Valhalla, New York 10595, USA.
Chem Res Toxicol. 1999 Sep;12(9):809-15. doi: 10.1021/tx980224j.
Several fluoroquinolone antibacterial agents exhibit an adverse phototoxic effect in humans and are photo-cocarcinogenic in mice. The UV-induced production of reactive oxygen species plays a role in the toxicity and may be involved in carcinogenicity. Four fluoroquinolones were examined for the ability to photochemically produce oxidative damage in naked DNA. The major structural difference in the fluoroquinolones that would have an effect on their photostability is the functionality at the 8-position. At this position, 1-cyclopropyl-7-(2,8-diazbicyclo[4.3.0]non-8-yl)-6, 8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (BAY y3118) contains a chlorine atom, lomefloxacin a fluorine atom, ciprofloxacin a proton, and moxifloxacin a methoxy group. The formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) in calf thymus DNA was assessed by HPLC with electrochemical detection, and strand breaks were measured in pBR322 with agarose gel electrophoresis. The relative photolability of the fluoroquinolones correlated to the extent of production of 8-oxodGuo and strand breaks, with both UVA and UVB irradiation, in the following order: BAY y3118 approximately lomefloxacin > ciprofloxacin > moxifloxacin. Experiments were performed to determine whether the mechanism of damage was due to a type I (radical) or type II (singlet oxygen) pathway. Nitrogen depletion of oxygen resulted in a decrease in the extent of formation of 8-oxodGuo, suggesting that oxygen was involved. The use of selective radical or singlet oxygen inhibitors was inconclusive with respect to which pathway was involved. The use of D(2)O as a solvent, which would extend the lifetime of singlet oxygen, suggested that this species is involved in the formation of 8-oxodGuo by moxifloxacin and ciprofloxacin, but not by lomefloxacin and BAY y3118. Similarly, it was found that singlet oxygen was not involved in strand break formation. Thus, the evidence suggests that fluoroquinolones can photochemically produce DNA damage by both type I and type II mechanisms.
几种氟喹诺酮类抗菌剂在人体中表现出不良的光毒性作用，并且在小鼠中具有光致癌性。紫外线诱导的活性氧生成在毒性中起作用，并且可能与致癌性有关。研究了四种氟喹诺酮类化合物对裸露DNA进行光化学氧化损伤的能力。氟喹诺酮类化合物中对其光稳定性有影响的主要结构差异在于8位的官能团。在这个位置，1-环丙基-7-(2,8-二氮杂双环[4.3.0]壬-8-基)-6,8-二氟-1,4-二氢-4-氧代-3-喹啉羧酸（BAY y3118）含有一个氯原子，洛美沙星含有一个氟原子，环丙沙星含有一个质子，莫西沙星含有一个甲氧基。通过高效液相色谱-电化学检测评估小牛胸腺DNA中8-氧代-7,8-二氢-2'-脱氧鸟苷（8-氧代dGuo）的形成，并通过琼脂糖凝胶电泳测量pBR322中的链断裂。在UVA和UVB照射下，氟喹诺酮类化合物的相对光解性与8-氧代dGuo的生成程度和链断裂程度相关，顺序如下：BAY y3118≈洛美沙星>环丙沙星>莫西沙星。进行实验以确定损伤机制是由于I型（自由基）还是II型（单线态氧）途径。氧气的氮气消耗导致8-氧代dGuo形成程度降低,表明氧气参与其中。关于涉及哪种途径，使用选择性自由基或单线态氧抑制剂尚无定论。使用D(2)O作为溶剂，这会延长单线态氧的寿命，表明该物质参与莫西沙星和环丙沙星形成8-氧代dGuo，但不参与洛美沙星和BAY y3118。同样，发现单线态氧不参与链断裂的形成。因此，证据表明氟喹诺酮类化合物可通过I型和II型机制光化学地产生DNA损伤。
