{"doi":"10.1177/0192623311432290","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":"<jats:p>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.</jats:p>","journal":"Toxicologic Pathology","year":2012,"id":601553,"datarank":0.5806801516361837,"base_score":3.8712010109078907,"endowment":3.8712010109078907,"self_citation_contribution":0.5806801516361837,"citation_network_contribution":0.0,"self_endowment_contribution":0.5806801516361837,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":47,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1542470,"name":"Miek Desmidt","orcid":null,"position":1,"is_corresponding":false},{"id":1542471,"name":"Geert R. Verheyen","orcid":null,"position":2,"is_corresponding":false},{"id":1542472,"name":"Sofie Starckx","orcid":null,"position":3,"is_corresponding":false},{"id":1542473,"name":"Siegrid Damsch","orcid":null,"position":4,"is_corresponding":false},{"id":1542474,"name":"Ronald De Vries","orcid":null,"position":5,"is_corresponding":false},{"id":1542475,"name":"Marc Verhemeldonck","orcid":null,"position":6,"is_corresponding":false},{"id":1542476,"name":"Jacky Van Gompel","orcid":null,"position":7,"is_corresponding":false},{"id":1542477,"name":"Ann Lampo","orcid":null,"position":8,"is_corresponding":false},{"id":1542478,"name":"Lieve Lammens","orcid":null,"position":9,"is_corresponding":false},{"id":1542469,"name":"Natalie Mesens","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"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":"<jats:p>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.</jats:p>","is_dataset_classified":null,"base_score":3.8712010109078907,"endowment":3.8712010109078907,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"22291062","pmcid":null,"openalex_id":"https://openalex.org/W2105659846","authors":[],"funders":[],"total_grants":0,"fwci":1.1799,"citation_percentile":0.78338267,"influential_citations":0,"citation_trend":[{"year":2012,"count":1},{"year":2014,"count":2},{"year":2015,"count":4},{"year":2016,"count":6},{"year":2017,"count":6},{"year":2018,"count":2},{"year":2019,"count":4},{"year":2020,"count":9},{"year":2021,"count":2},{"year":2022,"count":3},{"year":2023,"count":1},{"year":2024,"count":3},{"year":2025,"count":2},{"year":2026,"count":2}],"oa_status":"bronze","license":"https://journals.sagepub.com/page/policies/text-and-data-mining-license","oa_locations":[{"url":"https://journals.sagepub.com/doi/pdf/10.1177/0192623311432290","host_type":"journal"},{"url":"https://journals.sagepub.com/doi/pdf/10.1177/0192623311432290","host_type":"publisher"},{"url":"https://journals.sagepub.com/doi/full-xml/10.1177/0192623311432290","host_type":"publisher"},{"url":"https://doi.org/10.1177/0192623311432290","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/22291062","host_type":"repository"}],"fields_of_study":["Lysosomal Storage Disorders Research","Calcium signaling and nucleotide metabolism","Lipid Membrane Structure and Behavior","Amiodarone","Animals","Biomarkers","Cholesterol","Gene Expression Regulation","Glycerophospholipids","Lipid Metabolism","Lipidoses","Liver","Lung","Lymphocytes","Lysophospholipids","Male","Metabolic Networks and Pathways","Oligonucleotide Array Sequence Analysis","Organ Size","Phospholipids","Rats","Rats, Sprague-Dawley","Spleen","Toxicogenetics"],"mesh_terms":["Amiodarone","Animals","Cholesterol","Gene Expression Regulation","Lipidoses","Liver","Lung","Lymphocytes","Lysophospholipids","Male","Organ Size","Phospholipids","Spleen","Biomarkers","Rats, Sprague-Dawley","Glycerophospholipids","Oligonucleotide Array Sequence Analysis","Toxicogenetics","Lipid Metabolism","Rats","Metabolic Networks and Pathways"],"keywords":["Phospholipidosis","Monoacylglycerol lipase","NPC1","Endosome","Lysosome","Toxicogenomics","Biomarker","Cholesterol","Pharmacology","Chemistry","Lipid metabolism","Krabbe disease","Endocrinology","Biology","Internal medicine","Biochemistry","Medicine","Phospholipid","Cell","Membrane","Gene expression","Receptor","Endocannabinoid system","Gene","Disease","Leukodystrophy"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-29T16:43:05.289497Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}