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

Amiodarone

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Amiodarone	Peroxisome proliferator-activated receptor gamma	Protein	Humans	Unknown	Agonist	Details

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