title: Glucosylceramide and lysophosphatidylcholines as potential blood biomarkers for drug-induced hepatic phospholipidosis.
abstract: 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.
authors: Division of Medical Safety Science, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan.
authors: Kosuke
authors: K
authors: Saito
authors: Division of Medical Safety Science, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan maekawa@nihs.go.jp.
authors: Keiko
authors: K
authors: Maekawa
authors: Division of Medical Safety Science, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan.
authors: Masaki
authors: M
authors: Ishikawa
authors: Division of Medical Safety Science, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan.
authors: Yuya
authors: Y
authors: Senoo
authors: Division of Medical Safety Science, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan.
authors: Masayo
authors: M
authors: Urata
authors: Division of Medical Safety Science, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan.
authors: Mayumi
authors: M
authors: Murayama
authors: Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, Ibaraki, Osaka 567-0085, Japan.
authors: Noriyuki
authors: N
authors: Nakatsu
authors: Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, Ibaraki, Osaka 567-0085, Japan.
authors: Hiroshi
authors: H
authors: Yamada
authors: Division of Medical Safety Science, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan.
authors: Yoshiro
authors: Y
authors: Saito
mesh_terms: D000639:Amitriptyline; D000818:Animals; D001652:Bile Ducts / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000175:diagnosis / Q000209:etiology; D002853:Chromatography, Liquid; D002997:Clomipramine; D016002:Discriminant Analysis; D004195:Disease Models, Animal; D005963:Glucosylceramides / Q000097:blood*; D022781:Hepatocytes / Q000378:metabolism; D007099:Imipramine; D016018:Least-Squares Analysis; D008099:Liver / Q000378:metabolism*; D008244:Lysophosphatidylcholines / Q000097:blood*; D016464:Lysosomal Storage Diseases / Q000097:blood* / Q000139:chemically induced / Q000175:diagnosis; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics / Q000379:methods; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D051381:Rats
chemical_list: D015415:Biomarkers; D005963:Glucosylceramides; D008244:Lysophosphatidylcholines; D000639:Amitriptyline; D002997:Clomipramine; D007099:Imipramine
keywords: biomarker; ketoconazole; lipidomics; phospholipidosis; tricyclic antidepressant