Mechanism of phospholipidosis in amiodarone pulmonary toxicity.
Amiodarone therapy can be complicated by life-threatening pulmonary toxicity and is invariably associated with characteristic morphologic changes in the lung consistent with a severe phospholipidosis. To determine possible mechanisms, this study utilizes a unique in vitro cell culture model of amiodarone pulmonary toxicity and demonstrates that amiodarone can directly induce an accumulation of phospholipids within bovine pulmonary artery endothelial (BPAE) cells during the first 24 hr using amiodarone concentrations equivalent to concentrations found in the blood and lungs of human subjects. For example, amiodarone at 7.5 microM during a 24-hr incubation increases [32P]orthophosphate incorporation into phospholipids from 193 +/- 10 X 10(3) dpm/10(6) cells to 266 +/- 19 X 10(3) dpm/10(6) cells (P less than .01). A generalized increase in all phospholipids occurs after amiodarone treatment of the cultured cells; however, several specific phospholipids including phosphatidylinositol, phosphatidic acid and bis(monoacylglycerol) phosphate are all significantly increased to a greater extent than other phospholipids. Furthermore, the data indicate that amiodarone is a potent inhibitor of lysosomal phospholipase A1 and A2 activities derived from the BPAE cells; whereas, amiodarone has no effect on phospholipase A1 and A2 activities from the BPAE microsomal fraction. Thus, this study demonstrates phospholipids accumulate in cultured BPAE cells exposed to amiodarone and provides direct evidence that the drug initiates a specific and nearly complete inhibition of phospholipid degradation by lysosomal phospholipase A1 and A2 suggesting a similar process may occur in vivo in the lungs of subjects with amiodarone pulmonary toxicity.
Martin
W J
WJ
Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
Kachel
D L
DL
Vilen
T
T
Natarajan
V
V
D000638:Amiodarone / Q000633:toxicity*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010740:Phospholipases / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism*; D054466:Phospholipases A1; D010743:Phospholipids / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects
D010743:Phospholipids; D010740:Phospholipases; D010741:Phospholipases A; D054466:Phospholipases A1; D000638:Amiodarone