Does administration of hydroxychloroquine/amiodarone accelerate accumulation of globotriaosylceramide and globotriaosylsphingosine in Fabry mice?

Takahiro Tsukimura; Tomoko Shiga; Koki Saito; Yasuhiro Ogawa; Hitoshi Sakuraba; Tadayasu Togawa

doi:10.1016/j.ymgmr.2021.100773

Does administration of hydroxychloroquine/amiodarone accelerate accumulation of globotriaosylceramide and globotriaosylsphingosine in Fabry mice?

Mol Genet Metab Rep. 2021 May 29:28:100773. doi: 10.1016/j.ymgmr.2021.100773. eCollection 2021 Sep.

Authors

Takahiro Tsukimura¹, Tomoko Shiga², Koki Saito¹, Yasuhiro Ogawa³, Hitoshi Sakuraba², Tadayasu Togawa¹

Affiliations

¹ Department of Functional Bioanalysis, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
² Department of Clinical Genetics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
³ Department of Pharmacology, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.

Abstract

Drug-induced lysosomal storage disease (DILSD) caused by cationic amphiphilic drugs (CADs), which exhibits toxic manifestations and pathological findings mimicking Fabry disease (α-galactosidase A deficiency), has attracted the interests of clinicians and pathologists. Although the affected region is lysosomes in both the diseases, DILSD is characterized by intralysosomal accumulation of phospholipids and Fabry disease that of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3). However, it is unknown whether administration of CADs affects the catabolism of Gb3 and Lyso-Gb3 in Fabry disease. In this study, we independently administered hydroxychloroquine/amiodarone to wild-type and Fabry mice and examined the effects of the drugs on the enzyme activity and substrates accumulated in organs and tissues. The results revealed that the administration of the drugs induced accumulation of phosphatidylcholine in both the wild-type and Fabry mice. However, reduction of α-galactosidase A activity in the organs and tissues of the wild-type mice was not found, and the storage of Gb3 and Lyso-Gb3 was not accelerated by these drugs in the Fabry mice. This suggests that hydroxychloroquine/amiodarone do not have any significant impact on the catabolism of Gb3 and Lyso-Gb3 in organs and tissues of both wild-type and Fabry mice.

Keywords: Amiodarone; CAD, cationic amphiphilic drug; DILSD, drug-induced lysosomal storage disease; Drug-induced lysosomal storage disease; Fabry disease; Gb3, globotriaosylceramide; Globotriaosylceramide; Globotriaosylsphingosine; Hydroxychloroquine; ILV, intralysosomal luminal vesicle; LC, liquid chromatography; Lyso-Gb3, globotriaosylsphingosine; MRM, multiple reaction monitoring; MS/MS, tandem mass spectrometry; PhC, phosphatidylcholine; Phospholipid; α-Gal, α-galactosidase A; α-Galactosidase A.