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.
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.
authors.affiliation: Genetic and Exploratory Toxicology, Drug Safety Sciences, Janssen Pharmaceutical Companies of Johnson & Johnson, 2340 Beerse, Belgium. nmesens@its.jnj.com
authors.forename: Natalie
authors.initials: N
authors.lastname: Mesens
authors.forename: Miek
authors.initials: M
authors.lastname: Desmidt
authors.forename: Geert R
authors.initials: GR
authors.lastname: Verheyen
authors.forename: Sofie
authors.initials: S
authors.lastname: Starckx
authors.forename: Siegrid
authors.initials: S
authors.lastname: Damsch
authors.forename: Ronald
authors.initials: R
authors.lastname: De Vries
authors.forename: Marc
authors.initials: M
authors.lastname: Verhemeldonck
authors.forename: Jacky
authors.initials: J
authors.lastname: Van Gompel
authors.forename: Ann
authors.initials: A
authors.lastname: Lampo
authors.forename: Lieve
authors.initials: L
authors.lastname: Lammens
mesh_terms: D000638:Amiodarone / Q000633:toxicity*; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002784:Cholesterol / Q000097:blood; D005786:Gene Expression Regulation; D020404:Glycerophospholipids / Q000097:blood / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008064:Lipidoses / Q000097:blood / Q000139:chemically induced* / Q000652:urine; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D008246:Lysophospholipids / Q000097:blood* / Q000652:urine*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects; D010743:Phospholipids / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000473:pathology; D043922:Toxicogenetics
chemical_list: D015415:Biomarkers; D020404:Glycerophospholipids; D008246:Lysophospholipids; D010743:Phospholipids; C517624:didocosahexaenoyl bis(monoacylglycerol) phosphate; D002784:Cholesterol; D000638:Amiodarone