Phospholipidosis induced by PPARgamma signaling in human bronchial epithelial (BEAS-2B) cells exposed to amiodarone.
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Song M, Kim YJ, Ryu JC
Phospholipidosis induced by PPARgamma signaling in human bronchial epithelial (BEAS-2B) cells exposed to amiodarone.
Toxicol Sci. 2011 Mar;120(1):98-108. doi: 10.1093/toxsci/kfq361. Epub 2010 Dec 1.
- PubMed ID
- 21123845 [ View in PubMed]
- Abstract
Phospholipidosis (PL), a disorder characterized by an accumulation of phospholipids in lysosome-derived multilamellar vesicles owing to abnormal lipid metabolism. Amiodarone (AM), an antiarrhythmic drug, can induce pulmonary PL. First, to evaluate potential mechanisms of phospholipidosis, we found lipid metabolism--related genes by microarray. PPARG, FADS2, and SCD out of these genes were key genes in lipid metabolism and PPAR signaling by AM. The messenger RNA (mRNA) levels of PPARG, FADS2, and SCD were upregulated by AM. The PPARgamma antagonist GW9662 was used to investigate the possible involvement of PPARgamma as a mediator of AM-induced PL, and FADS2 and SCD small interfering RNAs (siRNAs) were used to examine the involvement of FADS2 and SCD in AM-induced PL. The inhibition of PPARgamma by GW9662 significantly attenuated the AM-induced upregulation of SCD and slightly decreased the AM-induced upregulation of FADS2. And the pretreatment of GW9662 significantly decreased the AM-induced uptake of the fluorescent phospholipid analog NBD-PC. The siRNA-mediated gene silencing of FADS2 and SCD also decreased the AM-induced NBD-PC uptake. These results suggest that the activation of the PPARgamma signaling pathway, including FADS2 and SCD, may play an important role in AM-induced PL. PPARG, FADS2, and SCD are AM-induced PL-related genes and may serve as potential biomarkers for PL caused by pulmonary toxicity. We also provide evidence for a possible mechanism of PL, the accumulation of phospholipid in the induction of FADS2 and SCD by PPARgamma, in AM-induced pulmonary toxicity.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Amiodarone Peroxisome proliferator-activated receptor gamma Protein Humans UnknownAgonistDetails - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Amiodarone Approved Investigational FADS2 9415 upregulated Amiodarone results in increased expression of FADS2 mRNA 11q12.2 Amiodarone Approved Investigational PPARG 5468 upregulated Amiodarone results in increased expression of PPARG mRNA 3p25.2 Amiodarone Approved Investigational SCD 6319 upregulated Amiodarone results in increased expression of SCD mRNA 10q24.31 Carbamazepine Approved Investigational FADS2 9415 downregulated Carbamazepine results in decreased expression of FADS2 mRNA 11q12.2 Carbamazepine Approved Investigational LDLR 3949 downregulated Carbamazepine results in decreased expression of LDLR mRNA 19p13.2 Carbamazepine Approved Investigational PCSK9 255738 downregulated Carbamazepine results in decreased expression of PCSK9 mRNA 1p32.3 Carbamazepine Approved Investigational SCD 6319 downregulated Carbamazepine results in decreased expression of SCD mRNA 10q24.31 Carbamazepine Approved Investigational SREBF2 6721 downregulated Carbamazepine results in decreased expression of SREBF2 mRNA 22q13.2