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- Title
Phospholipidosis in Rats Treated with Amiodarone: Serum Biochemistry and Whole Genome Micro-Array Analysis Supporting the Lipid Traffic Jam Hypothesis and the Subsequent Rise of the Biomarker BMP.
- Authors
Mesens, Natalie; Desmidt, Miek; Verheyen, Geert R.; Starckx, Sofie; Damsch, Siegrid; Vries, Ronald De; Verhemeldonck, Marc; Gompel, Jacky Van; Lampo, Ann; Lammens, Lieve
- Abstract
To provide mechanistic insight in the induction of phospholipidosis and the appearance of the proposed biomarker di-docosahexaenoyl (C22:6)-bis(monoacylglycerol) phosphate (BMP), rats were treated with 150 mg/kg amiodarone for 12 consecutive days and analyzed at three different time points (day 4, 9, and 12). Biochemical analysis of the serum revealed a significant increase in cholesterol and phospholipids at the three time points. Bio-analysis on the serum and urine detected a time-dependent increase in BMP, as high as 10-fold compared to vehicle-treated animals on day 12. Paralleling these increases, micro-array analysis on the liver of treated rats identified cholesterol biosynthesis and glycerophospholipid metabolism as highly modulated pathways. This modulation indicates that during phospholipidosis-induction interactions take place between the cationic amphiphilic drug and phospholipids at the level of BMP-rich internal membranes of endosomes, impeding cholesterol sorting and leading to an accumulation of internal membranes, converting into multilamellar bodies. This process shows analogy to Niemann-Pick disease type C (NPC). Whereas the NPC-induced lipid traffic jam is situated at the cholesterol sorting proteins NPC1 and NPC2, the amiodarone-induced traffic jam is thought to be located at the BMP level, demonstrating its role in the mechanism of phospholipidosis-induction and its significance for use as a biomarker.
- Subjects
TREATMENT of lipidoses; AMIODARONE; BIOMARKERS; MICROARRAY technology; BIOSYNTHESIS; BLOOD plasma; THERAPEUTICS
- Publication
Toxicologic Pathology, 2012, Vol 40, Issue 3, p491
- ISSN
0192-6233
- Publication type
Article
- DOI
10.1177/0192623311432290