Arachidonic acid‐containing phosphatidylcholine characterized by consolidated plasma and liver lipidomics as an early onset marker for tamoxifen‐induced hepatic phospholipidosis. Issue 8 (31st January 2017)

• Record Type: Journal Article
• Authors: Saito, Kosuke; Goda, Keisuke; Kobayashi, Akio; Yamada, Naohito; Maekawa, Kyoko; Saito, Yoshiro; Sugai, Shoichiro
• Is Part Of: Journal of applied toxicology. Volume 37:Issue 8(2017)
• Page Start: 943
• Page End: 953
• Publication Date: 2017-01-31
• Subjects: Lipidomics -- biomarker -- phospholipidosis -- tamoxifen -- plasma–liver association; Toxicology -- Periodicals; Industrial toxicology -- Periodicals; Environmentally induced diseases -- Periodicals; Toxicology -- Periodicals; 615.9005
• DOI: 10.1002/jat.3442
• Languages: English
• ISSNs: 0260-437X

Abstract

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. Abstract : The present study demonstrated the tamoxifen‐induced alteration of the plasma and liver lipid profiles in Sprague–Dawley rats. At a stage of hepatic phospholipidosis (PLD) caused by tamoxifen, arachidonic acid (AA)‐containing phosphatidylcholines (PCs) were commonly reduced in both plasma and liver and the reduction was linearly associated. We also demonstrated the reduction of AA‐containing PCs in the pre‐PLD stage. Moreover, free AA levels were decreased by tamoxifen treatment. Our study demonstrated that AA‐containing PCs might be potential biomarkers for tamoxifen‐induced PLD.