Chouini-Lalanne N, Defais M, Paillous N
Laboratoire des IMRCP, UMR 5623, Université Paul Sabatier, Toulouse, France.
Biochem Pharmacol. 1998 Feb 15;55(4):441-6. doi: 10.1016/s0006-2952(97)00511-x.
Phototoxic nonsteroidal antiinflammatory drugs (NSAIDs) may induce DNA damage in vitro upon irradiation. In this study, we investigated the ability of ketoprofen (KP), tiaprofenic acid (Tia), naproxen (NP) and indomethacin (IND) to photosensitize the formation of pyrimidine dimers and single strand breaks. Both kinds of damage were sought by analyzing DNA-drug mixtures irradiated at 313 nm by agarose gel electrophoresis. The formation of pyrimidine dimers was evidenced by using endonuclease V from bacteriophage T4 and compared to that induced by acetophenone, a well-known photosensitizer of thymine dimerization. Upon irradiation of DNA alone, pyrimidine dimers were observed while single strand breaks were not detected under our conditions. DNA, in the presence of NSAIDs, undergoes single strand breaks, the quantum yield of the DNA cleavage so induced (phiC) varying from 5 x 10(-4) for KP to 10(-5) for IND. The formation of dimers was only increased in the presence of KP or Tia. The quantum yields of pyrimidine dimers formed by photosensitization (phiD) were 2 x 10(-4) for KP and 10(-5) for Tia, respectively. The oxygen and concentration dependence of both processes was analyzed in the case of KP. In aerated solution, KP-photoinduced cleavage of DNA was predominant on the photodimerization process of pyrimidines, whereas in deaerated solution the cleavage was decreased and the dimerization increased. These results reflect competition between a radical process leading to DNA cleavage and a poorly efficient energy transfer between the drug and the pyrimidines at the origin of the dimerization process.
光毒性非甾体抗炎药（NSAIDs）在体外受照射时可能会诱导DNA损伤。在本研究中，我们研究了酮洛芬（KP）、噻洛芬酸（Tia）、萘普生（NP）和吲哚美辛（IND）使嘧啶二聚体形成和单链断裂光敏化的能力。通过琼脂糖凝胶电泳分析在313nm照射的DNA-药物混合物来寻找这两种损伤。使用来自噬菌体T4的核酸内切酶V证实了嘧啶二聚体的形成，并与由苯乙酮（一种众所周知的胸腺嘧啶二聚化光敏剂）诱导的情况进行了比较。单独照射DNA时，观察到嘧啶二聚体，而在我们的条件下未检测到单链断裂。在NSAIDs存在下，DNA会发生单链断裂，如此诱导的DNA切割的量子产率（phiC）从KP的5×10⁻⁴到IND的10⁻⁵不等。仅在KP或Tia存在时二聚体的形成才会增加。通过光敏化形成的嘧啶二聚体的量子产率（phiD）对于KP分别为2×10⁻⁴，对于Tia为10⁻⁵。在KP的情况下分析了这两个过程的氧和浓度依赖性。在通气溶液中，KP光诱导的DNA切割在嘧啶的光二聚化过程中占主导，而在脱气溶液中切割减少且二聚化增加。这些结果反映了导致DNA切割的自由基过程与二聚化过程起始时药物与嘧啶之间低效的能量转移之间的竞争。
