Doß Sandra, Blessing Corinne, Haller Katharina, Richter Georg, Sauer Martin
Department Extracorporeal Therapy Systems (EXTHER), Fraunhofer Institute for Cell Therapy and Immunology, Schillingallee 68, 18057 Rostock, Germany.
Department of Anesthesiology and Intensive Care Medicine, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany.
Curr Issues Mol Biol. 2022 Oct 3;44(10):4639-4657. doi: 10.3390/cimb44100317.
(1) Antibiotics are an important weapon in the fight against serious bacterial infections and are considered a common cause of drug-induced liver injury (DILI). The hepatotoxicity of many drugs, including antibiotics, is poorly analyzed in human in vitro models. (2) A standardized assay with a human hepatoma cell line was used to test the hepatotoxicity of various concentrations (Cmax, 5× Cmax, and 10× Cmax) of antibiotics. In an ICU, the most frequently prescribed antibiotics, ampicillin, cefepime, cefuroxime, levofloxacin, linezolid, meropenem, rifampicin, tigecycline, and vancomycin, were incubated with HepG2/C3A cells for 6 days. Cell viability (XTT assay, LDH release, and vitality), albumin synthesis, and cytochrome 1A2 activity were determined in cells. (3) In vitro, vancomycin, rifampicin, and tigecycline showed moderate hepatotoxic potential. The antibiotics ampicillin, cefepime, cefuroxime, levofloxacin, linezolid, and meropenem were associated with mild hepatotoxic reactions in test cells incubated with the testes Cmax concentration. Rifampicin and cefuroxime showed significantly negative effects on the viability of test cells. (4) Further in vitro studies and global pharmacovigilance reports should be conducted to reveal underlying mechanism of the hepatotoxic action of vancomycin, rifampicin, tigecycline, and cefuroxime, as well as the clinical relevance of these findings.
（1）抗生素是对抗严重细菌感染的重要武器，被认为是药物性肝损伤（DILI）的常见原因。包括抗生素在内的许多药物的肝毒性在人体体外模型中分析不足。（2）使用一种标准化的人肝癌细胞系检测法来测试不同浓度（Cmax、5×Cmax和10×Cmax）抗生素的肝毒性。在重症监护病房（ICU），将最常处方的抗生素氨苄西林、头孢吡肟、头孢呋辛、左氧氟沙星、利奈唑胺、美罗培南、利福平、替加环素和万古霉素与HepG2/C3A细胞孵育6天。测定细胞的活力（XTT检测、乳酸脱氢酶释放和活力）、白蛋白合成及细胞色素1A2活性。（3）在体外，万古霉素、利福平和替加环素显示出中度肝毒性潜力。在以Cmax浓度孵育的测试细胞中，抗生素氨苄西林、头孢吡肟、头孢呋辛、左氧氟沙星、利奈唑胺和美罗培南与轻度肝毒性反应相关。利福平和头孢呋辛对测试细胞的活力显示出显著的负面影响。（4）应开展进一步的体外研究和全球药物警戒报告，以揭示万古霉素、利福平、替加环素和头孢呋辛肝毒性作用的潜在机制，以及这些发现的临床相关性。
