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.

Comparison of Effects of Diet on Mammary Cancer: Efficacy of Various Preventive Agents and Metabolomic Changes of Different Diets and Agents

“…3C and D), levels of the glycolipid palmitoyl-linoleoyl-glycerophosphocholine (2) were increased, whereas the levels of stearoyl-arachidonoyl-glycerophosphocholine (1) were decreased in the Tamoxifen-treated rats on either diet. The glycolipids changes in tamoxifen have been observed previously (25) and may be related to known alterations in glycolipid levels associated with tamoxifen in humans (31).…”

Anabolic androgenic steroids exert a selective remodeling of the plasma lipidome that mirrors the decrease of the de novo lipogenesis in the liver

“…Furthermore, it is known that estrogen receptor 2 upregulates the synthesis of arachidonic acid (Ariazi et al 2011). This effect of estrogens is mediated by fatty acids desaturases (FADSs) (Ariazi et al 2011;Saito et al 2017). In this context, it seems plausible that the supratherapeutic doses of nandrolone decanoate and testosterone undecanoate in our study activate the estrogen receptor after aromatization (Simpson et al 2002).…”

“…Highly unsaturated triacylglycerides and PC(40:8) (putatively PC(20:4/20:4) (Balgoma et al 2010a, b)) are upregulated in a model of estrogen-related endometriosis (Dutta et al 2016). Tamoxifen (an inhibitor of estrogen effect) decreases triacylglycerides with highly unsaturated fatty acids in the liver and in plasma (Saito et al 2017). Furthermore, it is known that estrogen receptor 2 upregulates the synthesis of arachidonic acid (Ariazi et al 2011).…”

Evaluation of the Potential Risk of Drugs to Induce Hepatotoxicity in Human—Relationships between Hepatic Steatosis Observed in Non-Clinical Toxicity Study and Hepatotoxicity in Humans-

“…To sort these lipid ions, |w| > 0.05 and |p (corr)| > 0.8 in the loading s-plot of the OPLS-DA score, which represent the magnitude of contribution (weight) and reliability (correlation), respectively, were selected as cut-off values. Subsequently, the lipid ions identified as discriminant factors were subjected to identification of lipid molecules as described previously [30,31]. …”