2014年10月
Glucosylceramide and Lysophosphatidylcholines as Potential Blood Biomarkers for Drug-Induced Hepatic Phospholipidosis
TOXICOLOGICAL SCIENCES
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- 巻
- 141
- 号
- 2
- 開始ページ
- 377
- 終了ページ
- 386
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1093/toxsci/kfu132
- 出版者・発行元
- OXFORD UNIV PRESS
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.
- リンク情報
- ID情報
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- DOI : 10.1093/toxsci/kfu132
- ISSN : 1096-6080
- eISSN : 1096-0929
- PubMed ID : 24980264
- Web of Science ID : WOS:000343045100008