In vitro inhibition of lysosomal phospholipase A1 of rat lung by amiodarone and desethylamiodarone
Identifieur interne : 003201 ( Main/Exploration ); précédent : 003200; suivant : 003202In vitro inhibition of lysosomal phospholipase A1 of rat lung by amiodarone and desethylamiodarone
Auteurs : Karl Y. Hostetler [États-Unis] ; Jacqueline R. Giordano [États-Unis] ; Elisabeth J. Jellison [États-Unis]Source :
- Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism [ 0005-2760 ] ; 1988.
Descripteurs français
- KwdFr :
- Amiodarone (analogues et dérivés), Amiodarone (pharmacologie), Animaux, Chromatographie en phase liquide à haute performance, Lysosomes (enzymologie), Mâle, Phospholipases (antagonistes et inhibiteurs), Phospholipases A (antagonistes et inhibiteurs), Phospholipases A1, Poumon (enzymologie), Poumon (ultrastructure), Rats, Rats de lignée F344, Solubilité.
- MESH :
- analogues et dérivés : Amiodarone.
- antagonistes et inhibiteurs : Phospholipases, Phospholipases A.
- enzymologie : Lysosomes, Poumon.
- pharmacologie : Amiodarone.
- ultrastructure : Animaux, Chromatographie en phase liquide à haute performance, Mâle, Phospholipases A1, Poumon, Rats, Rats de lignée F344, Solubilité.
English descriptors
- KwdEn :
- Amiodarone (analogs & derivatives), Amiodarone (pharmacology), Animals, Chromatography, High Pressure Liquid, Lung (enzymology), Lung (ultrastructure), Lysosomes (enzymology), Male, Phospholipases (antagonists & inhibitors), Phospholipases A (antagonists & inhibitors), Phospholipases A1, Rats, Rats, Inbred F344, Solubility.
- MESH :
- chemical , analogs & derivatives : Amiodarone.
- chemical , antagonists & inhibitors : Phospholipases, Phospholipases A.
- chemical , pharmacology : Amiodarone.
- enzymology : Lung, Lysosomes.
- ultrastructure : Lung.
- Teeft :
- Acid phospholipase, Amiodarone, Animals, Assay, Chromatography, High Pressure Liquid, Desethylamiodarone, Equal amounts, Hostetler, Lung lysosomal phospholipase, Lung tissue, Lysosomal, Lysosomal phospholipase, Lysosome, Male, Mitochondrial, Mitochondrion, Oleic acid, Pellet, Phospholipase, Phospholipases A1, Potent inhibitors, Protein content, Rats, Rats, Inbred F344, Solubility.
Abstract
Abstract: Amiodarone causes phospholipid storage in the lysosomes of various types of lung cell in animals and man. It has been proposed that this is due to its ability to inhibit lysosomal phospholipase A. To investigate this further, a crude lysosomal fraction from rat lung was prepared and phospholipase A was isolated and its positional specificity was determined. Analysis of the products formed after incubation with 2-[1-14C]oleoylphosphatidylcholine showed that only phospholipase A1 activity is present. This soluble preparation of lung lysosomal phospholipase A1 was used to study inhibition by amiodarone and desethylamiodarone, in vitro. Both were extremely potent inhibitors of the lung acid phospholipase A1. To evaluate the levels of amiodarone in lung lysosomes, rats were treated with the agent for 3 days and the combined mitochondrial/ lysosomal fraction of lung tissue was prepared by differential centrifugation. This fraction had been shown previously to be highly enriched in amiodarone. Purified mitochondria and lysosomes were isolated from the combined mitochondrial/lysosomal fraction with Percoll gradients and analyzed for their drug content by HPLC. Amiodarone and desethylamiodarone were present in roughly equal amounts, relative to protein, in mitochondria and lysosomes, respectively. Amiodarone appears to differ from other cationic amphiphilic drugs which cause lipidosis because the latter are more highly lysosomotropic. Although amiodarone does not appear to be highly lysosomotropic in lung, it causes lysosomal phospholipid storage because of its ability to concentrate in lung and because it inhibits lysosomal phospholipase A to a much greater extent than other cationic amphiphiles such as diethylaminoethoxyhexestrol, chloroquine and chlorphentermine.
Url:
DOI: 10.1016/0005-2760(88)90205-6
Affiliations:
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It has been proposed that this is due to its ability to inhibit lysosomal phospholipase A. To investigate this further, a crude lysosomal fraction from rat lung was prepared and phospholipase A was isolated and its positional specificity was determined. Analysis of the products formed after incubation with 2-[1-14C]oleoylphosphatidylcholine showed that only phospholipase A1 activity is present. This soluble preparation of lung lysosomal phospholipase A1 was used to study inhibition by amiodarone and desethylamiodarone, in vitro. Both were extremely potent inhibitors of the lung acid phospholipase A1. To evaluate the levels of amiodarone in lung lysosomes, rats were treated with the agent for 3 days and the combined mitochondrial/ lysosomal fraction of lung tissue was prepared by differential centrifugation. This fraction had been shown previously to be highly enriched in amiodarone. Purified mitochondria and lysosomes were isolated from the combined mitochondrial/lysosomal fraction with Percoll gradients and analyzed for their drug content by HPLC. Amiodarone and desethylamiodarone were present in roughly equal amounts, relative to protein, in mitochondria and lysosomes, respectively. Amiodarone appears to differ from other cationic amphiphilic drugs which cause lipidosis because the latter are more highly lysosomotropic. Although amiodarone does not appear to be highly lysosomotropic in lung, it causes lysosomal phospholipid storage because of its ability to concentrate in lung and because it inhibits lysosomal phospholipase A to a much greater extent than other cationic amphiphiles such as diethylaminoethoxyhexestrol, chloroquine and chlorphentermine.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Californie</li></region><settlement><li>San Diego</li></settlement></list><tree><country name="États-Unis"><region name="Californie"><name sortKey="Hostetler, Karl Y" sort="Hostetler, Karl Y" uniqKey="Hostetler K" first="Karl Y." last="Hostetler">Karl Y. Hostetler</name></region><name sortKey="Giordano, Jacqueline R" sort="Giordano, Jacqueline R" uniqKey="Giordano J" first="Jacqueline R." last="Giordano">Jacqueline R. Giordano</name><name sortKey="Jellison, Elisabeth J" sort="Jellison, Elisabeth J" uniqKey="Jellison E" first="Elisabeth J." last="Jellison">Elisabeth J. Jellison</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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