Glucosylceramide and Lysophosphatidylcholines as Potential Blood Biomarkers for Drug-Induced Hepatic Phospholipidosis
| Autor: | Masayo Urata, Hiroshi Yamada, Mayumi Murayama, Kosuke Saito, Yoshiro Saito, Noriyuki Nakatsu, Masaki Ishikawa, Keiko Maekawa, Yuya Senoo |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
Drug Imipramine medicine.medical_specialty Amitriptyline media_common.quotation_subject Pharmacology Glucosylceramides Toxicology Mass Spectrometry Predictive Value of Tests Internal medicine Lipidomics medicine Animals Metabolomics Least-Squares Analysis media_common chemistry.chemical_classification Phospholipidosis Discriminant Analysis Lysophosphatidylcholines Rats Lysosomal Storage Diseases Disease Models Animal Endocrinology Liver chemistry Clomipramine Multivariate Analysis Hepatocytes Biomarker (medicine) Ketoconazole Bile Ducts Chemical and Drug Induced Liver Injury Biomarkers Chromatography Liquid Tricyclic medicine.drug |
| Zdroj: | Toxicological Sciences. 141:377-386 |
| ISSN: | 1096-0929 1096-6080 |
| DOI: | 10.1093/toxsci/kfu132 |
| Popis: | Drug-induced phospholipidosis is one of the major concerns in drug development and clinical treatment. The present study involved the use of a nontargeting lipidomic analysis with liquid chromatography-mass spectrometry to explore noninvasive blood biomarkers for hepatic phospholipidosis from rat plasma. We used three tricyclic antidepressants (clomipramine [CPM], imipramine [IMI], and amitriptyline [AMT]) for the model of phospholipidosis in hepatocytes and ketoconazole (KC) for the model of phospholipidosis in cholangiocytes and administered treatment for 3 and 28 days each. Total plasma lipids were extracted and measured. Lipid molecules contributing to the separation of control and drug-treated rat plasma in a multivariate orthogonal partial least squares discriminant analysis were identified. Four lysophosphatidylcholines (LPCs) (16:1, 18:1, 18:2, and 20:4) and 42:1 hexosylceramide (HexCer) were identified as molecules separating control and drug-treated rats in all models of phospholipidosis in hepatocytes. In addition, 16:1, 18:2, and 20:4 LPCs and 42:1 HexCer were identified in a model of hepatic phospholipidosis in cholangiocytes, although LPCs were identified only in the case of 3-day treatment with KC. The levels of LPCs were decreased by drug-induced phospholipidosis, whereas those of 42:1 HexCer were increased. The increase in 42:1 HexCer was much higher in the case of IMI and AMT than in the case of CPM; moreover, the increase induced by IMI was dose-dependent. Structural characterization determining long-chain base and hexose delineated that 42:1 HexCer was d18:1/24:0 glucosylceramide (GluCer). In summary, our study demonstrated that d18:1/24:0 GluCer and LPCs are potential novel biomarkers for drug-induced hepatic phospholipidosis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|