Department of Anesthesiology, Central Japan International Medical Center, Minokamo, Japan.
Asahi University School of Dentistry, Mizuho, Japan.
Med Princ Pract. 2022;31(2):111-117. doi: 10.1159/000524210. Epub 2022 Mar 22.
Although 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.
Liposomal 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.
Acetaminophen 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.
In comparison with phenacetin, lipid composition-dependent membrane interactivity of acetaminophen could be related to nephrotoxicity but not to analgesic activity and hepatotoxicity.
尽管对乙酰氨基酚是最广泛使用的非处方药物之一，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。我们假设对乙酰氨基酚可能作用于神经、肝和肾的细胞膜。为了验证这一假设，我们通过比较结构相关的非那西汀来研究对乙酰氨基酚与仿生类脂双层膜的相互作用。
用磷脂和胆固醇制备含有单层囊泡的脂质体（悬浮在 pH7.4 的缓冲液中），以模拟神经元细胞、肝细胞和肾细胞的膜脂质组成。它们与临床相关浓度的对乙酰氨基酚和非那西汀反应，然后测量荧光偏振以确定它们对膜流动性的膜相互作用。
对乙酰氨基酚和非那西汀与神经模拟和肝模拟膜相互作用，在 10-100μM 时增加膜流动性。两种药物在使肝模拟膜流动化方面比神经模拟膜更有效。虽然在神经模拟和肝模拟膜中，相对膜相互作用的效力是非那西汀>对乙酰氨基酚，但这种膜效应与它们的相对镇痛和肝毒性作用相冲突。对乙酰氨基酚和非那西汀与肾模拟膜强烈相互作用，在 2-100μM 和 0.1-100μM 时分别增加膜流动性。与对乙酰氨基酚相比，非那西汀在较低浓度（<2μM）时与肾模拟膜显著相互作用，这与它们的相对肾毒性作用一致。
与非那西汀相比，对乙酰氨基酚的脂质组成依赖性膜相互作用可能与肾毒性有关，而与镇痛活性和肝毒性无关。
