Different Mechanisms for the Photoinduced Production of Oxidative DNA Damage by Fluoroquinolones Differing in Photostability
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- 作者：Thomas E. Spratt ; Sherri S. Schultz ; Douglas E. Levy ; Di Chen ; Gerhardt Schlü ; ter ; and Gary M. Williams
- 刊名：Chemical Research in Toxicology
- 出版年：1999
- 出版时间：September 1999
- 年：1999
- 卷：12
- 期：9
- 页码：809 - 815
- 全文大小：139K
- 年卷期：v.12,no.9(September 1999)
- ISSN：1520-5010
文摘
Several fluoroquinolone antibacterial agents exhibit an adverse phototoxic effect in humansand are photo-cocarcinogenic in mice. The UV-induced production of reactive oxygen speciesplays a role in the toxicity and may be involved in carcinogenicity. Four fluoroquinolones wereexamined for the ability to photochemically produce oxidative damage in naked DNA. Themajor structural difference in the fluoroquinolones that would have an effect on theirphotostability 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 moxifloxacina methoxy group. The formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) in calfthymus DNA was assessed by HPLC with electrochemical detection, and strand breaks weremeasured in pBR322 with agarose gel electrophoresis. The relative photolability of thefluoroquinolones correlated to the extent of production of 8-oxodGuo and strand breaks, withboth UVA and UVB irradiation, in the following order: BAY y3118 ~ 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. Nitrogendepletion of oxygen resulted in a decrease in the extent of formation of 8-oxodGuo, suggestingthat oxygen was involved. The use of selective radical or singlet oxygen inhibitors wasinconclusive with respect to which pathway was involved. The use of D2O as a solvent, whichwould extend the lifetime of singlet oxygen, suggested that this species is involved in theformation of 8-oxodGuo by moxifloxacin and ciprofloxacin, but not by lomefloxacin and BAYy3118. Similarly, it was found that singlet oxygen was not involved in strand break formation.Thus, the evidence suggests that fluoroquinolones can photochemically produce DNA damageby both type I and type II mechanisms.