Acetaminophen Has Lipid Composition-Dependent Membrane Interactivity That Could be Related to Nephrotoxicity but Not to Analgesic Activity and Hepatotoxicity
Acetaminophen Has Lipid Composition-Dependent Membrane Interactivity That Could be Related to Nephrotoxicity but Not to Analgesic Activity and Hepatotoxicity
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对乙酰氨基酚具有脂质成分依赖性膜相互作用，可能与肾毒性有关，但与镇痛活性和肝毒性无关
DOI：
10.1159/000524210
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发表时间：
2022
影响因子：
3.2
通讯作者：
Maki Mizogami and Hironori Tsuchiya
中科院分区：
文献类型：
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作者：
Takeshima Hideyuki;Niwa Tohru;Yamashita Satoshi;Takamura-Enya Takeji;Iida Naoko;Wakabayashi Mika;Nanjo Sohachi;Abe Masanobu;Sugiyama Toshiro;Kim Young-Joon;Ushijima Toshikazu;Maki Mizogami and Hironori Tsuchiya
虽然对乙酰氨基酚是最广泛使用的非处方药之一，但这种经典药物发挥镇痛、肝毒性和肾毒性作用的机制仍不清楚。我们推测醋氨酚可能作用于神经、肝脏和肾脏的细胞膜。为了验证这一假设，我们研究了对乙酰氨基酚与仿生脂质双层membranes.MethodsLiposomal膜（单层囊泡悬浮在pH 7.4的缓冲液中）的相互作用，通过比较结构相关的非那西丁制备与磷脂和胆固醇模仿神经细胞，肝细胞和肾细胞的膜脂质组合物。他们进行了反应与对乙酰氨基酚和非那西丁在临床相关的浓度，然后通过测量荧光偏振，以确定其膜的相互作用，以修改membranefluidity.ResultsAcetaminophen和非那西丁相互作用与neuro-mimetic和hepat-mimetic膜，以增加膜流动性在10-100 μM。这两种药物更有效地流化肝模拟膜比神经模拟膜。虽然在拟神经和拟肝膜中，相对膜相互作用效力为非那西丁>>对乙酰氨基酚，但这种膜效应与其相对镇痛和肝毒性效应相冲突。对乙酰氨基酚和非那西丁分别在2-100 μM和0.1-100 μM时与拟肾膜强烈相互作用，增加膜流动性。非那西丁在较低的浓度（< 2 μM）下与拟肾细胞膜的相互作用显著高于对乙酰氨基酚，这与它们的相对肾毒性效应一致。结论与非那西丁相比，对乙酰氨基酚的脂质成分依赖性膜相互作用可能与肾毒性有关，但与镇痛活性和肝毒性无关。
ObjectiveAlthough acetaminophen is one of the most widely used over-the-counter drugs, the mechanisms by which this classical drug exerts analgesic, hepatotoxic, and nephrotoxic effects remain unclear. We hypothesized that acetaminophen might act on cellular membranes of nerves, liver, and kidneys. In order to verify this hypothesis, we studied the interactivity of acetaminophen with biomimetic lipid bilayer membranes by comparing with structurally related phenacetin.MethodsLiposomal membranes (unilamellar vesicles suspended in the buffer of pH 7.4) were prepared with phospholipids and cholesterol to mimic the membrane lipid composition of neuronal cells, hepatocytes, and nephrocytes. They were subjected to reactions with acetaminophen and phenacetin at clinically relevant concentrations, followed by measuring fluorescence polarization to determine their membrane interactivity to modify membrane fluidity.ResultsAcetaminophen and phenacetin interacted with neuro-mimetic and hepato-mimetic membranes to increase membrane fluidity at 10–100 μM. Both drugs were more effective in fluidizing hepato-mimetic membranes than neuro-mimetic membranes. Although the relative membrane-interacting potency was phenacetin>> acetaminophen in neuro-mimetic and hepato-mimetic membranes, such membrane effects conflicted with their relative analgesic and hepatotoxic effects. Acetaminophen and phenacetin strongly interacted with nephro-mimetic membranes to increase membrane fluidity at 2–100 μM and 0.1–100 μM, respectively. Phenacetin interacted significantly with nephro-mimetic membranes at lower concentrations (< 2 μM) than acetaminophen, which was consistent with their relative nephrotoxic effects.ConclusionIn comparison with phenacetin, lipid composition-dependent membrane interactivity of acetaminophen could be related to nephrotoxicity but not to analgesic activity and hepatotoxicity.