Kavčič H, Jug U, Mavri J, Umek N
Clinical Department for Anesthesiology and Surgical Intensive Therapy, University Medical Center Ljubljana, Ljubljana, Slovenia.
Department of Anesthesiology and Reanimatology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Front Chem. 2023 Jun 20;11:1208843. doi: 10.3389/fchem.2023.1208843. eCollection 2023.
Local anesthetics are widely recognized pharmaceutical compounds with various clinical effects. Recent research indicates that they positively impact the antioxidant system and they may function as free radical scavengers. We hypothesize that their scavenging activity is influenced by the lipophilicity of the environment. We assessed the free radical scavenging capacity of three local anesthetics (lidocaine, bupivacaine, and ropivacaine) using ABTS, DPPH, and FRAP antioxidant assays. We also employed quantum chemistry methods to find the most probable reaction mechanism. The experiments were conducted in an aqueous environment simulating extracellular fluid or cytosol, and in a lipophilic environment (-octanol) simulating cellular membranes or myelin sheets. All local anesthetics demonstrated ABTS˙ radical scavenging activity, with lidocaine being the most effective. Compared to Vitamin C, lidocaine exhibited a 200-fold higher half-maximal inhibitory concentration. The most thermodynamically favorable and only possible reaction mechanism involved hydrogen atom transfer between the free radical and the -C-H vicinal to the carbonyl group. We found that the antioxidant activity of all tested local anesthetics was negligible in lipophilic environments, which was further confirmed by quantum chemical calculations. Local anesthetics exhibit modest free radical scavenging activity in aqueous environments, with lidocaine demonstrating the highest activity. However, their antioxidant activity in lipophilic environments, such as cellular membranes, myelin sheets, and adipose tissue, appears to be negligible. Our results thus show that free radical scavenging activity is influenced by the lipophilicity of the environment.
局部麻醉药是一类具有多种临床作用且被广泛认可的药物化合物。最近的研究表明，它们对抗氧化系统有积极影响，并且可能起到自由基清除剂的作用。我们推测它们的清除活性受环境亲脂性的影响。我们使用ABTS、DPPH和FRAP抗氧化测定法评估了三种局部麻醉药（利多卡因、布比卡因和罗哌卡因）的自由基清除能力。我们还采用量子化学方法来寻找最可能的反应机制。实验在模拟细胞外液或细胞质的水性环境中以及模拟细胞膜或髓鞘的亲脂性环境（正辛醇）中进行。所有局部麻醉药均表现出ABTS˙自由基清除活性，其中利多卡因最为有效。与维生素C相比，利多卡因的半数最大抑制浓度高200倍。最热力学有利且唯一可能的反应机制涉及自由基与羰基邻位的-C-H之间的氢原子转移。我们发现，在亲脂性环境中，所有测试局部麻醉药的抗氧化活性都可以忽略不计，量子化学计算进一步证实了这一点。局部麻醉药在水性环境中表现出适度的自由基清除活性，其中利多卡因活性最高。然而，它们在细胞膜、髓鞘和脂肪组织等亲脂性环境中的抗氧化活性似乎可以忽略不计。因此，我们的结果表明自由基清除活性受环境亲脂性的影响。
