title: Arachidonic acid-containing phosphatidylcholine characterized by consolidated plasma and liver lipidomics as an early onset marker for tamoxifen-induced hepatic phospholipidosis.
abstract: Lipid profiling has emerged as an effective approach to not only screen disease and drug toxicity biomarkers but also understand their underlying mechanisms of action. Tamoxifen, a widely used antiestrogenic agent for adjuvant therapy against estrogen-positive breast cancer, possesses side effects such as hepatic steatosis and phospholipidosis (PLD). In the present study, we administered tamoxifen to Sprague-Dawley rats and used lipidomics to reveal tamoxifen-induced alteration of the hepatic lipid profile and its association with the plasma lipid profile. Treatment with tamoxifen for 28 days caused hepatic PLD in rats. We compared the plasma and liver lipid profiles in treated vs. untreated rats using a multivariate analysis to determine differences between the two groups. In total, 25 plasma and 45 liver lipids were identified and altered in the tamoxifen-treated group. Of these lipids, arachidonic acid (AA)-containing phosphatidylcholines (PCs), such as PC (17:0/20:4) and PC (18:1/20:4), were commonly reduced in both plasma and liver. Conversely, tamoxifen increased other phosphoglycerolipids in the liver, such as phosphatidylethanolamine (18:1/18:1) and phosphatidylinositol (18:0/18:2). We also examined alteration of AA-containing PCs and some phosphoglycerolipids in the pre-PLD stage and found that these lipid alterations were initiated before pathological alteration in the liver. In addition, changes in plasma and liver levels of AA-containing PCs were linearly associated. Moreover, levels of free AA and mRNA levels of AA-synthesizing enzymes, such as fatty acid desaturase 1 and 2, were decreased by tamoxifen treatment. Therefore, our study demonstrated that AA-containing PCs might have potential utility as novel and predictive biomarkers for tamoxifen-induced PLD. Copyright © 2017 John Wiley & Sons, Ltd.
authors.affiliation: Division of Medicinal Safety Science, National Institute of Health Sciences, Setagaya, Tokyo, 158-8501, Japan.
authors.forename: Kosuke
authors.identifier: 0000-0002-1035-3454
authors.initials: K
authors.lastname: Saito
authors.affiliation: Toxicology Research Lab, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Hadano, Kanagawa, 257-0024, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Goda
authors.affiliation: Toxicology Research Lab, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Hadano, Kanagawa, 257-0024, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Kobayashi
authors.affiliation: Toxicology Research Lab, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Hadano, Kanagawa, 257-0024, Japan.
authors.forename: Naohito
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Division of Medicinal Safety Science, National Institute of Health Sciences, Setagaya, Tokyo, 158-8501, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Maekawa
authors.affiliation: Division of Medicinal Safety Science, National Institute of Health Sciences, Setagaya, Tokyo, 158-8501, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Toxicology Research Lab, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Hadano, Kanagawa, 257-0024, Japan.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Sugai
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000097:blood* / Q000378:metabolism; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D050356:Lipid Metabolism / Q000187:drug effects; D008064:Lipidoses / Q000139:chemically induced / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010713:Phosphatidylcholines / Q000097:blood* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000633:toxicity*
chemical_list: D015415:Biomarkers; D010713:Phosphatidylcholines; D013629:Tamoxifen; D016718:Arachidonic Acid
keywords: Lipidomics; biomarker; phospholipidosis; plasma-liver association; tamoxifen