Detection of metabolic activation leading to drug-induced phospholipidosis in rat hepatocyte spheroids

The Journal of Toxicological Sciences
Masashi TakagiShigeru Ohta

Abstract

Drug-induced phospholipidosis (PLD) is one of the adverse reactions to treatment with cationic amphiphilic drugs. Recently, simple and reliable evaluation methods for PLD have been reported. However, the predictive power of these methods for in vivo PLD induction is insufficient in some cases. To accurately predict PLD, we focused on drug metabolism and used three-dimensional cultures of hepatocytes known as spheroids. Here we used the fluorescent phospholipid dye N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine (NBD-PE) to detect PLD induction. After 48 hr exposure to 20 µM amiodarone and amitriptyline, PLD inducers, NBD-PE fluorescence in the spheroids was significantly higher than that in the control. In contrast, 1 mM acetaminophen, as a negative control, did not increase fluorescence. Furthermore, the combination of NBD-PE fluorescence and LysoTracker Red fluorescence and the accumulation of intrinsic phospholipids reflected PLD induction in spheroids. To evaluate metabolic activation, we assessed PLD induction by loratadine. NBD-PE fluorescence intensity was significantly increased by 50 µM loratadine treatment. However, the fluorescence was markedly decreased by co-treatment with ...Continue Reading

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Citations

Jan 13, 2018·Frontiers in Oncology·Frédérique MittlerMaxim Y Balakirev
May 19, 2020·Critical Reviews in Toxicology·Xihui ZhangLeshuai W Zhang
Sep 15, 2017·The Journal of Toxicological Sciences·Takafumi TomidaMasahiro Iwaki
Jun 5, 2021·Journal of Lipid Research·Vania Hinkovska-GalchevaJames A Shayman

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