Teschke Rolf
Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, 63450 Hanau, Germany.
Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt am Main, 60590 Frankfurt am Main, Germany.
Biomedicines. 2024 Sep 27;12(10):2208. doi: 10.3390/biomedicines12102208.
Idiosyncratic drug-induced liver injury (iDILI) by flucloxacillin presents as both cholestatic and hepatocellular injury. Its mechanistic steps are explored in the present analysis as limited data exist on the cascade of events leading to iDILI in patients with an established diagnosis assessed for causality by the Roussel Uclaf Causality Assessment Method (RUCAM). Studies with human liver microsomes showed that flucloxacillin is a substrate of cytochrome P450 (CYP) with ist preferred isoforms CYP 3A4/3A7 that toxified flucloxacillin toward 5'-hydroxymethylflucloxacillin, which was cytotoxic to human biliary epithelial cell cultures, simulating human cholestatic injury. This provided evidence for a restricted role of the metabolic CYP-dependent hypothesis. In contrast, 5'-hydroxymethylflucloxacillin generated metabolically via CYP 3A4/3A7 was not cytotoxic to human hepatocytes due to missing genetic host features and a lack of non-parenchymal cells, including immune cells, which commonly surround the hepatocytes in the intact liver in abundance. This indicated a mechanistic gap regarding the clinical hepatocellular iDILI, now closed by additional studies and clinical evidence based on HLA B57:01-positive patients with iDILI by flucloxacillin and a verified diagnosis by the RUCAM. Naïve T-cells from volunteers expressing HLA B57:01 activated by flucloxacillin when the drug antigen was presented by dendritic cells provided the immunological basis for hepatocellular iDILI caused by flucloxacillin. HLA B*57:01-restricted activation of drug-specific T-cells caused covalent binding of flucloxacillin to albumin acting as a hapten. Following drug stimulation, T-cell clones expressing CCR4 and CCR9 migrated toward CCL17 and CCL25 and secreted interferon-γ and cytokines. In conclusion, cholestatic injury can be explained metabolically, while hepatocellular injury requires both metabolic and immune activation.
氟氯西林所致的特异质性药物性肝损伤（iDILI）表现为胆汁淤积性和肝细胞性损伤。由于对于经罗塞尔·优克福因果关系评估方法（RUCAM）评估因果关系的确诊患者中导致iDILI的一系列事件的数据有限，因此在本分析中探讨了其机制步骤。用人肝微粒体进行的研究表明，氟氯西林是细胞色素P450（CYP）的底物，其首选同工型为CYP 3A4/3A7，该同工型将氟氯西林转化为5'-羟甲基氟氯西林，后者对人胆管上皮细胞培养物具有细胞毒性，模拟了人类胆汁淤积性损伤。这为代谢性CYP依赖性假说的有限作用提供了证据。相比之下，通过CYP 3A4/3A7代谢产生的5'-羟甲基氟氯西林对人肝细胞没有细胞毒性，这是由于缺乏遗传宿主特征以及缺乏非实质细胞，包括免疫细胞，而在完整肝脏中免疫细胞通常大量围绕在肝细胞周围。这表明在临床肝细胞性iDILI方面存在机制上的空白，现在通过基于氟氯西林所致iDILI的HLA B57:01阳性患者的进一步研究和临床证据以及经RUCAM验证的诊断得以填补。当药物抗原由树突状细胞呈递时，来自表达HLA B57:
