Soldevila Sonia, Cuquerella M Consuelo, Bosca Francisco
Instituto Universitario Mixto de Tecnologia Quimica (UPV-CSIC), Universitat Politecnica de Valencia , Avenida de los Naranjos s/n, 46022 Valencia, Spain.
Chem Res Toxicol. 2014 Apr 21;27(4):514-23. doi: 10.1021/tx400377s. Epub 2014 Feb 26.
Although the phototoxic and photoallergic properties of fluoroquinolone antibiotics (FQ) are remarkable, the mechanisms involved in these processes are not completely understood. For this reason, it is considered worthwhile to study in detail the photochemical interactions of lomefloxacin (LFX) and its N-acetyl derivative ALFX, two 6,8-dihalogenated fluoroquinolones, with the most abundant protein in human plasma (human serum albumin, HSA) to analyze their covalent binding. Fluorescence measurements and laser flash photolysis experiments performed in this work have revealed that N-acetylation of the LFX piperazinyl moiety produces an important increase of the drug affinity to albumin. Thus, while the association constant (Ka) for the LFX···HSA complex is below 10(3) M(-1), the Ka for the HSA···ALFX complex resulted in ca. 5 × 10(3) M(-1). Interestingly, LFX is mainly located at site I of HSA, while ALFX shows no preference for site I or II. A high reactivity between the aryl cations generated from (A)LFX dehalogenation and Trp and Tyr together with the generation of covalent adducts between the FQ and these amino acids was observed. However, the interactions between the FQ singlet excited state and albumin in FQ···HSA complexes seem to be the key process of FQ covalent binding to albumin. Moreover, our findings have shown a correlation between the photobinding properties of dihalogenated fluoroquinolones to HSA and their FQ···HSA association constants.
尽管氟喹诺酮类抗生素（FQ）具有显著的光毒性和光过敏特性，但这些过程所涉及的机制尚未完全明确。因此，详细研究洛美沙星（LFX）及其N - 乙酰衍生物ALFX（两种6,8 - 二卤代氟喹诺酮）与人体血浆中含量最丰富的蛋白质（人血清白蛋白，HSA）的光化学相互作用，以分析它们的共价结合，被认为是有价值的。在这项工作中进行的荧光测量和激光闪光光解实验表明，LFX哌嗪基部分的N - 乙酰化使药物对白蛋白的亲和力显著增加。因此，虽然LFX···HSA复合物的缔合常数（Ka）低于10³ M⁻¹，但HSA···ALFX复合物的Ka约为5 × 10³ M⁻¹。有趣的是，LFX主要位于HSA的位点I，而ALFX对位点I或II没有偏好。观察到（A）LFX脱卤产生的芳基阳离子与色氨酸和酪氨酸之间具有高反应活性，同时FQ与这些氨基酸之间生成了共价加合物。然而，FQ···HSA复合物中FQ单重激发态与白蛋白之间的相互作用似乎是FQ与白蛋白共价结合的关键过程。此外，我们的研究结果表明二卤代氟喹诺酮与HSA的光结合特性与其FQ···HSA缔合常数之间存在相关性。
