title: Biomarkers to monitor drug-induced phospholipidosis.
abstract: Di-docosahexaenoyl (C22:6)-bis(monoacylglycerol) phosphate (BMP) was identified as a promising phospholipidosis (PL) biomarker in rats treated with either amiodarone, gentamicin, or azithromycin. Sprague-Dawley rats received either amiodarone (150 mg/kg), gentamicin (100 mg/kg) or azithromycin (30 mg/kg) once daily for ten consecutive days. Histopathological examination of tissues by transmission electron microscopy (TEM) indicated different degrees of accumulation of phospholipidosis in liver, lung, mesenteric lymph node, and kidney of drug-treated rats but not controls. Liquid chromatography coupled to mass spectrometry (LC/MS) was used to identify levels of endogenous biochemical profiles in rat urine. Urinary levels of di-docosahexaenoyl (C22:6)-bis(monoacylglycerol) phosphate (BMP) correlated with induction of phospholipidosis for amiodarone, gentamicin and azithromycin. Rats treated with gentamicin also had increased urinary levels of several phosphatidylinositol (PI), phosphatidylcholine (PC), and phosphatidylethanolamine (PE) species.
authors.affiliation: Nextcea, Inc., 3 Goffe Road, Lexington, MA 02421, USA.
authors.forename: Elizabeth Tengstrand
authors.initials: ET
authors.lastname: Baronas
authors.forename: Ju-Whei
authors.initials: JW
authors.lastname: Lee
authors.forename: Carl
authors.initials: C
authors.lastname: Alden
authors.forename: Frank Y
authors.initials: FY
authors.lastname: Hsieh
mesh_terms: D000638:Amiodarone / Q000009:adverse effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D017963:Azithromycin / Q000009:adverse effects; D015415:Biomarkers / Q000652:urine; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D005839:Gentamicins / Q000009:adverse effects; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008064:Lipidoses / Q000139:chemically induced / Q000473:pathology / Q000652:urine*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008246:Lysophospholipids / Q000652:urine*; D008279:Magnetic Resonance Imaging; D008297:Male; D008854:Microscopy, Electron; D010713:Phosphatidylcholines / Q000652:urine; D010714:Phosphatidylethanolamines / Q000652:urine; D010716:Phosphatidylinositols / Q000652:urine; D010743:Phospholipids / Q000652:urine*; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013997:Time Factors
chemical_list: D000889:Anti-Arrhythmia Agents; D000900:Anti-Bacterial Agents; D015415:Biomarkers; D005839:Gentamicins; D008246:Lysophospholipids; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010716:Phosphatidylinositols; D010743:Phospholipids; C517624:didocosahexaenoyl bis(monoacylglycerol) phosphate; C483858:phosphatidylethanolamine; D017963:Azithromycin; D000638:Amiodarone