基于脂质组学技术筛选碘克沙醇皮肤毒性生物标志物及其潜在靶点研究

doi:10.19803/j.1672-8629.20240615

摘要/Abstract

摘要： 目的探究碘克沙醇引起皮肤毒性的脂质生物标志物及其潜在干预靶点。方法收集安徽医科大学附属六安医院2020年12月31日至2023年12月31日期间使用碘克沙醇的患者48例,根据有无皮疹反应分为无皮疹组和皮疹组,每组24例。对患者血清进行脂质谱检测,并利用Metaboanalyst 6.0软件分析差异表达的脂质分子,并进行受试者工作特征曲线（Receiver Operating Characteristic Curve, ROC）分析。随后分别从基因集数据库（Molecular Signatures Database, MSigDB）和美国国家生物技术信息中心（National Center for Biotechnology Information, NCBI）下载脂代谢相关基因和皮肤毒性相关转录组测序结果,对两者进行交集,筛选碘克沙醇导致皮疹的潜在脂代谢靶点。结果与无皮疹患者相比,脂质谱结果显示,共鉴定出198种脂类。经差异脂质成分筛选,最后筛选出67个具有显著差异的脂质成分,包括甘油二酯（Diacylglycerol, DG）、甘油三酯（Triacylglycerol, TG）、双（单酰基甘油）磷酸酯（Bis-Monoacylglycerol-Phosphate, BMP）、胆固醇酯（Cholesterol Esters, CE）和磷脂酰乙醇胺（Phosphatidylethanolamine, PE）等。与无皮疹组患者相比,皮疹组患者血清中DG、TG、BMP、CE和PE水平均明显升高,而烷基磷脂酰胆碱[Alkyl-Phosphatidylcholine, PC（O）]、纤浆磷脂酰胆碱[Plasmenyl-Phosphatidylcholine, PC（P）]和醚联磷脂酰乙醇胺[Ether-Linked Phosphatidylethanolamine, PE（O）]水平则显著下降。在排名前20位的差异脂质分子中,TG类脂质分子占比最高,达55%（11/20）。ROC-AUC曲线分析显示筛选出的差异脂质成分具有较好的预测效能（AUC >0.800）。将药物所致皮疹患者的差异基因与从 MSigDB中下载并整理得到脂代谢相关基因集进行交集得出131个脂代谢相关差异基因（包括61个上调基因和70个下调基因）。进一步分析发现,在排名前20位的差异基因中,蛋白脂蛋白2（Proteolipid Protein2,PLP2）升高最为显著。结论血脂TG可能是介导碘克沙醇所致皮疹发生的潜在生物标志物,其机制可能与脂代谢基因PLP2表达异常升高有关。

关键词: 碘克沙醇, 皮疹, 脂质组学, 甘油二酯, 甘油三酯, 双（单酰基甘油）磷酸酯, 胆固醇酯, 磷脂酰乙醇胺, 蛋白脂蛋白2

Abstract: Objective To explore lipid biomarkers and potential intervention targets for skin toxicity caused by iodixanol. Methods Forty-eight patients using iodixanol in our hospital were selected and divided into a no rash group and a rash group, with 24 cases in each group. Lipid mass spectrometry was adopted to detect the serum of patients with skin toxicity of iodixanol, differentially expressed lipid molecules were analyzed using Metaboanalyst 6.0 software, and the receiver operating characteristic curve (ROC) was drawn. Subsequently, lipid metabolism related genes and transcriptome sequencing results related to skin toxicity were downloaded from the molecular signatures database (MSigDB) and the National Center for Biotechnology Information (NCBI) in the United States, and the intersections of the above two datasets were examined to identify potential lipid metabolism targets associated with iodixanol induced rash. Results Compared with patients without rash, the lipid profile results showed that a total of 198 lipids were identified. After the screening of differential lipid components, 67 lipid components with significant differences were finally identified, including diacylglycerol (DG), triacylglycerol (TG), bis-monoacylglycerol-phosphate (BMP), cholesterol esters (CE), and phosphatidylethanolamine (PE). Compared with patients without rash, the levels of DG, TG, BMP, CE, and PE in the serum of patients with rash were significantly increased while the levels of alkyl-phosphatidylcholine [PC (O)], plasmenyl-phosphatidylcholine [PC (P)], and ether-linked phosphatidylethanolamine [PE (O)] were significantly decreased. Among the top 20 differentially expressed lipid molecules, lipid molecules of TG were dominating, accounting for 55% (11/20). ROC analysis showed that the screened differential lipid components had good predictability (AUC>0.800). Further analysis revealed that among the top 20 differentially expressed genes, proteolipid protein2 (PLP2) showed the most significant increase. Conclusion Levels of lipid TG may be a potential biomarker mediating the occurrence of skin rash caused by iodixanol, and the mechanism may be related to the abnormal upregulation of lipid metabolism gene PLP2 expression.

Key words: Ioxanol, Rash, Lipidomics, Diacylglycerol, Triacylglycerol, Bis-Monoacylglycerol-Phosphate, Cholesterol Esters, Phosphatidylethanolamine, Proteolipid Protein 2

中图分类号:

R981
R994.11

饶玲, 许甜甜, 何春远, 王芳, 王法财. 基于脂质组学技术筛选碘克沙醇皮肤毒性生物标志物及其潜在靶点研究[J]. 中国药物警戒, 2025, 22(4): 403-409.

RAO Ling, XU Tiantian, HE Chunyuan, WANG Fang, WANG Facai. Screening of Biomarkers of Skin Toxicity of Ioxanol and Its Potential Targets Based on Lipidomics[J]. Chinese Journal of Pharmacovigilance, 2025, 22(4): 403-409.

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