Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia.
Drug Dev Res. 2019 Jun;80(4):475-480. doi: 10.1002/ddr.21520. Epub 2019 Jan 30.
An overdose of acetaminophen (APAP) causes liver injury in experimental animals and humans. The activation step (formation of reactive metabolite, N-acetyl-p-benzoquinone imine by cytochrome P450 system) and the consequent downstream pathway of oxidative stress, nitrosative stress, and inflammation play an important role in APAP-induced hepatotoxicity. Formulation of APAP with an inhibitor of the activation step would be ideal to prevent accidental and intentional APAP toxicity. Dimethyl sulfoxide (DMSO) is a common colorless, inexpensive solvent, and considered safe in human. We hypothesized that a less hepatotoxic APAP if co-formulated with DMSO. To test this hypothesis, C57BL/6 mice were given toxic dose of APAP (250 mg kg , i.p.) mixed with different doses of DMSO (25, 50, 100, and 200 μl kg ). Six hours after APAP treatment, blood and lives were collected for analysis. In DMSO treated groups, there was dose-dependent decrease in markers of liver injury, alanine aminotransferase, and aspartate aminotransferase. Maximum protection was obtained with 200 μl DMSO kg . DMSO was shown to inhibit the activation step by decreasing the rate of GSH depletion in vivo and inhibiting cytochrome P450 system in vitro. Also the levels of lipid peroxides, nitrate/nitrite, tumor necrosis factor-alpha, and interleukin 1β were decreased significantly. In conclusion, DMSO exerts its protective action by inhibiting the metabolic activation of APAP and thus alleviating the downstream, oxidative stress, nitrosative stress, and inflammation via indirect inhibition. Our findings suggest that replacing the current APAP with APAP/DMSO formulation could prevent accidental and intentional APAP toxicity.
对乙酰氨基酚（APAP）过量会导致实验动物和人类的肝损伤。激活步骤（细胞色素 P450 系统形成活性代谢物 N-乙酰对苯醌亚胺）和随后的氧化应激、硝化应激和炎症下游途径在 APAP 诱导的肝毒性中起重要作用。用激活步骤抑制剂将 APAP 制成配方将是预防意外和故意 APAP 毒性的理想选择。二甲基亚砜（DMSO）是一种常见的无色、廉价的溶剂，在人类中被认为是安全的。我们假设，如果与 DMSO 共同配制，APAP 的肝毒性会降低。为了验证这一假设，用不同剂量的 DMSO（25、50、100 和 200μl/kg）将 C57BL/6 小鼠与毒性剂量的 APAP（250mg/kg，ip）混合，给予 C57BL/6 小鼠。APAP 处理 6 小时后，采集血液和肝脏进行分析。在 DMSO 处理组中，肝损伤标志物丙氨酸氨基转移酶和天冬氨酸氨基转移酶的水平呈剂量依赖性下降。用 200μl/kg DMSO 获得最大保护。DMSO 通过降低体内 GSH 耗竭率和体外抑制细胞色素 P450 系统来抑制激活步骤。此外，脂质过氧化物、硝酸盐/亚硝酸盐、肿瘤坏死因子-α和白细胞介素 1β的水平也显著降低。总之，DMSO 通过抑制 APAP 的代谢激活来发挥其保护作用，从而通过间接抑制减轻下游氧化应激、硝化应激和炎症。我们的研究结果表明，用 APAP/DMSO 配方代替目前的 APAP 可以预防意外和故意的 APAP 毒性。
