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.