中性双氯芬酸引起磷脂双层显著变化：与胃毒性机制相关。
Neutral Diclofenac Causes Remarkable Changes in Phosphatidylcholine Bilayers: Relevance for Gastric Toxicity Mechanisms.
机构信息
LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal (C.P.-L., S.K.J., J.P.A., C.N., S.R.); Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil (C.P.-L., I.M.C.); IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico (A.C., M.P.) and Departamento de Química e Bioquímica, Faculdade de Ciências (A.C.), Universidade de Lisboa, Lisboa, Portugal
LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal (C.P.-L., S.K.J., J.P.A., C.N., S.R.); Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil (C.P.-L., I.M.C.); IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico (A.C., M.P.) and Departamento de Química e Bioquímica, Faculdade de Ciências (A.C.), Universidade de Lisboa, Lisboa, Portugal.
出版信息
Mol Pharmacol. 2020 Apr;97(4):295-303. doi: 10.1124/mol.119.118299. Epub 2020 Feb 26.
The main objective of this study was to clarify the topical mechanisms underlying diclofenac-induced gastric toxicity by considering for the first time both ionization states of this nonsteroidal anti-inflammatory drug. 1,2-Dimyristoyl--glycero-3-phosphocholine (DMPC) liposomes were the model system chosen to mimic the protective phospholipid layers of the gastric mucosa and to describe the interactions with diclofenac, considering the pH gradient found in the gastric mucosa (3 < pH < 7.4). Complementary experimental techniques were combined to evaluate the drug's affinity for DMPC bilayers, as well as to assess the drug's effects on the structural properties of the phospholipid bilayer. The diclofenac-DMPC interactions were clearly dependent on the drug's ionization state. Neutral diclofenac displayed greater affinity for DMPC bilayers than anionic diclofenac. Moreover, the protonated/neutral form of the drug induced more pronounced and/or distinct alterations in the structure of the DMPC bilayer than the deprotonated/ionized form, considering similar membrane concentrations. Therefore, neutral diclofenac-induced changes in the structural properties of the external phospholipid layers of the gastric mucosa may constitute an additional toxicity mechanism of this worldwide-used drug, which shall be considered for the development of safer therapeutic strategies. SIGNIFICANCE STATEMENT: Neutral or anionic diclofenac exerted distinct alterations in phosphatidylcholine bilayers, which are used in this work as models for the protective phospholipid layers of the gastric mucosa. Remarkable changes were induced by neutral diclofenac in the structural properties of the phospholipid bilayer, suggesting that both ionized and neutral states of nonsteroidal anti-inflammatory drugs must be considered to clarify their mechanisms of toxicity and to ultimately develop safer anti-inflammatory drugs.
本研究的主要目的是阐明双氯芬酸引起胃毒性的局部机制，首次同时考虑到这种非甾体抗炎药的两种电离状态。1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱（DMPC）脂质体被选为模拟胃黏膜保护性磷脂层的模型系统，并考虑到胃黏膜中发现的 pH 梯度（3 < pH < 7.4），描述与双氯芬酸的相互作用。将互补的实验技术结合起来，评估药物对 DMPC 双层的亲和力，以及评估药物对磷脂双层结构特性的影响。双氯芬酸-DMPC 的相互作用明显取决于药物的电离状态。中性双氯芬酸对 DMPC 双层的亲和力大于阴离子双氯芬酸。此外，与去质子化/离子化形式相比，考虑到类似的膜浓度，药物的质子化/中性形式诱导 DMPC 双层结构更明显和/或更明显的改变。因此，中性双氯芬酸诱导胃黏膜外磷脂层结构性质的变化可能构成这种全球使用药物的另一种毒性机制，在开发更安全的治疗策略时应加以考虑。意义陈述：中性或阴离子双氯芬酸对磷脂双层施加了明显的改变，在这项工作中，这些双层被用作胃黏膜保护性磷脂层的模型。中性双氯芬酸对磷脂双层结构特性引起了显著的变化，这表明非甾体抗炎药的离子化和中性状态都必须被考虑，以阐明其毒性机制，并最终开发更安全的抗炎药。
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