Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, 8006 Zurich, Switzerland.
Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
Int J Mol Sci. 2023 Feb 3;24(3):3013. doi: 10.3390/ijms24033013.
Sphingolipids are exceptionally diverse, comprising hundreds of unique species. The bulk of circulating sphingolipids are synthesized in the liver, thereby plasma sphingolipid profiles represent reliable surrogates of hepatic sphingolipid metabolism and content. As changes in plasma sphingolipid content have been associated to exposure to drugs inducing hepatotoxicity both in vitro and in rodents, in the present study the translatability of the preclinical data was assessed by analyzing the plasma of patients with suspected drug-induced liver injury (DILI) and control subjects. DILI patients, whether intrinsic or idiosyncratic cases, had no alterations in total sphingoid base levels and profile composition compared to controls, whereby cardiovascular disease (CVD) was a confounding factor. Upon exclusion of CVD individuals, elevation of 1-deoxysphingosine (1-deoxySO) in the DILI group emerged. Notably, 1-deoxySO values did not correlate with ALT values. While 1-deoxySO was elevated in all DILI cases, only intrinsic DILI cases concomitantly displayed reduction of select shorter chain sphingoid bases. Significant perturbation of the sphingolipid metabolism observed in this small exploratory clinical study is discussed and put into context, in the consideration that sphingolipids might contribute to the onset and progression of DILI, and that circulating sphingoid bases may function as mechanistic markers to study DILI pathophysiology.
鞘脂类化合物具有极高的多样性，包含数百种独特的种类。大部分循环鞘脂类化合物是在肝脏中合成的，因此血浆鞘脂类谱代表了肝脏鞘脂代谢和含量的可靠替代物。由于血浆鞘脂类含量的变化与体外和啮齿动物中诱导肝毒性的药物暴露有关，在本研究中，通过分析疑似药物性肝损伤（DILI）患者和对照者的血浆，评估了临床前数据的可转化性。与对照组相比，无论是固有型还是特发型 DILI 患者的总鞘氨醇碱基水平和谱组成都没有改变，而心血管疾病（CVD）是一个混杂因素。在排除 CVD 个体后，DILI 组中 1-脱氧鞘氨醇（1-deoxySO）的水平升高。值得注意的是，1-deoxySO 值与 ALT 值不相关。虽然 1-deoxySO 在所有 DILI 病例中均升高，但只有固有型 DILI 病例同时显示选择较短链鞘氨醇碱基的减少。在这项小型探索性临床研究中观察到的鞘脂代谢显著紊乱被讨论并置于背景中，考虑到鞘脂类可能有助于 DILI 的发生和进展，并且循环鞘氨醇碱基可能作为研究 DILI 病理生理学的机制标志物发挥作用。
