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

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.

Does administration of hydroxychloroquine/amiodarone affect the efficacy of enzyme replacement therapy for Fabry mice?

“…cf.) The α-Gal activities in the livers, kidneys, and hearts of wild-type mice were 26 ± 4, 17 ± 1, and 4 ± 0 nmol/h/mg protein [n = 4], respectively [ 22 ]. α-Gal: α-galactosidase A, HCQ: hydroxychloroquine, AMI: amiodarone, ERT: enzyme replacement therapy.…”

“…The Gb3 contents in the livers, kidneys, and hearts of wild-type mice were 1.0 ± 0.0, 15 ± 3, and 0.5 ± 0.0 μg/g [n = 4], respectively [ 22 ]. The Lyso-Gb3 contents in the livers, kidneys, and hearts of wild-type mice were 0.08 ± 0.01, 0.08 ± 0.01, and 0.09 ± 0.02 nmol/g [n = 4], respectively [ 22 ]. HCQ: hydroxychloroquine, AMI: amiodarone, Gb3: globotriaosylceramide, Lyso-Gb3: globotriaosylsphingosine, ERT: enzyme replacement therapy.…”

“…The contents of Gb3 and Lyso-Gb3 in samples were determined by means of liquid chromatography (LC)-tandem mass spectrometry (MS/MS), according to the method described previously [ 22 ]. Briefly, 10 μL of a sample was mixed with a 70 μL aliquot of chloroform:methanol (1:2), and then a 10 μL aliquot of 5 μg/mL Gb3 (C17:0) and a 10 μL aliquot of 500 nmol/L stable isotope-labelled Lyso-Gb3 were added as the internal standards.…”

In Vivo Delivery of Therapeutic Molecules by Transplantation of Genome-Edited Induced Pluripotent Stem Cells

“…For measurement of Gb3 and Lys-Gb3 in organs and tissues of mice, a liquid chromatography (LC)-tandem mass spectrometry (MS/MS) analysis was performed according to a previous report 24 . Briefly, the organs and tissues were homogenized in MES buffer, and a 10-µl aliquot of the homogenate was mixed with a 70-µl aliquot of chloroform: methanol (1:2).…”

In VivoDelivery of Therapeutic Molecules by Transplantation of Genome-Edited Induced Pluripotent Stem Cells

“…For measurement of Gb3 and Lys-Gb3 in organs and tissues of mice, a liquid chromatography (LC)-tandem mass spectrometry (MS/MS) analysis was performed according to a previous report (Tsukimura et al, 2021). Briefly, the organs and tissues were homogenized in MES buffer, and a 10 µl aliquot of the homogenate was mixed with a 70 µl aliquot of chloroform: methanol (1:2).…”