Liu Xiang, Chen Chen, Zhang Xiaoying
Chinese-German Joint Laboratory for Natural Product Research, College of Biological Science and Engineering, Shaanxi University of Technology, Hanzhong 723001, P.R. China.
Centre of Molecular and Environmental Biology University of Minho, Department of Biology, Campus de Gualtar, Braga, 4710-057, Portugal.
Int J Med Sci. 2020 Feb 4;17(3):414-421. doi: 10.7150/ijms.38527. eCollection 2020.
Acetaminophen (APAP) and roxithromycin (ROX) are often used in combination in clinical practice. To evaluate their drug-drug interactions (DDIs) and the hepatotoxicity of co-administration, rats were randomly separated into four groups: Control, APAP (50 mg/kg), ROX (5.5 mg/kg) and APAP-ROX (50 mg/kg and 5.5 mg/kg, respectively). The pharmacokinetic parameters between APAP and ROX were assayed by HPLC, and a cocktail method was used to evaluate the activities of cytochrome (CYP) 450. The liver microsome CYP2E1 protein was detected using Western blot. The levels of plasma parameters, mRNA levels of inflammatory factors (TNF-α, INF-γ, VCAM-1, CXCL-1 and STAT-3) and antioxidant factors (Nrf-2, GSTA, GCLC-1, HO-1 and NQO1) were determined using real-time PCR, along with the observation on histopathological changes in the liver tissue. APAP and ROX co-treatment significantly increased CYP2E1 activity, decreased CYP2D6 activity and prolonged APAP and ROX clearance. Co-treatment increased mRNA expressions of TNF-α, NQO1 and MDA while decreasing GPX and SOD levels. Histopathological evidence showed the changes of liver tissues in terms of structure, size and tight arrangement. This study confirmed that a combination of APAP and ROX inhibited APAP metabolism and that the peak concentration of ROX was delayed. The resulting high level of CYP2E1 may induce oxidative stress and cause liver damage.
对乙酰氨基酚（APAP）和罗红霉素（ROX）在临床实践中常联合使用。为评估它们之间的药物相互作用（DDIs）以及联合用药的肝毒性，将大鼠随机分为四组：对照组、APAP（50 mg/kg）组、ROX（5.5 mg/kg）组和APAP-ROX组（分别为50 mg/kg和5.5 mg/kg）。采用高效液相色谱法测定APAP和ROX之间的药代动力学参数，并使用鸡尾酒法评估细胞色素（CYP）450的活性。采用蛋白质免疫印迹法检测肝微粒体CYP2E1蛋白。使用实时聚合酶链反应测定血浆参数水平、炎症因子（TNF-α、INF-γ、VCAM-1、CXCL-1和STAT-3）和抗氧化因子（Nrf-2、GSTA、GCLC-1、HO-1和NQO1）的mRNA水平，并观察肝组织的组织病理学变化。APAP和ROX联合治疗显著增加CYP2E1活性，降低CYP2D6活性，并延长APAP和ROX的清除时间。联合治疗增加了TNF-α、NQO1和丙二醛的mRNA表达，同时降低了谷胱甘肽过氧化物酶（GPX）和超氧化物歧化酶（SOD）水平。组织病理学证据显示肝组织在结构、大小和紧密排列方面发生了变化。本研究证实，APAP和ROX联合使用会抑制APAP代谢，且ROX的峰值浓度延迟出现。由此产生的高水平CYP2E1可能诱导氧化应激并导致肝损伤。
