title: Silymarin and vitamin E reduce amiodarone-induced lysosomal phospholipidosis in rats.
abstract: Several antioxidants have been shown to reduce lysosomal phospholipidosis, which is a potential mechanism of amiodarone toxicity, and prevent amiodarone toxicity by antioxidant and/or non-antioxidant mechanisms. The aim of this study was to test whether the co-administration of two structurally different antioxidants vitamin E and silymarin with amiodarone can reduce amiodarone-induced lysosomal phospholipidosis, and if yes, by reducing the tissue concentration of amiodarone and desethylamiodarone or by their antioxidant action. To this end, male Fischer 344 rats were treated by gavage once a day for 3 weeks and randomly assigned to the following four experimental groups: 1, control; 2, amiodarone (150 mg/(kg per day)); 3, amiodarone (150 mg/(kg per day)) plus vitamin E (100 mg/(kg per day)); 4, amiodarone (150 mg/(kg per day)) plus silymarin (60 mg/(kg per day)) treated groups. Total plasma phospholipid (PL), liver-conjugated diene, thiobarbituric acid reactive substances (TBARSs), amiodarone and desethylamiodarone concentrations were determined and the extent of lysosomal phospholipidosis in the liver was estimated by a semi-quantitative electron microscopic method. Amiodarone treatment increased significantly the liver-conjugated diene (P<0.001), TBARS (P=0.012), plasma total PL (P<0.001) concentrations compared with control. Antioxidants combined with amiodarone significantly decreased the liver-conjugated diene (P<0.001 for both), TBARS (P=0.016 for vitamin E, P=0.053 borderline for silymarin) and plasma total PL (P=0.058 borderline for vitamin E, P<0.01 for silymarin) concentrations compared with amiodarone treatment alone. Silymarin significantly (P=0.021) reduced liver amiodarone, but only tended to decrease desethylamiodarone concentration; however, vitamin E failed to do so. Amiodarone treatment increased lysosomal phospholipidosis (P<0.001) estimated by semi-quantitative electron microscopic method and both antioxidants combined with amiodarone reduced significantly (P<0.001 for both) the amiodarone-induced lysosomal phospholipidosis. In conclusion, silymarin presumably reduced lysosomal phospholipidosis by both antioxidant action and its liver amiodarone concentration decreasing effect, while vitamin E exerted similar effect by antioxidant action alone. Thus, both antioxidant action and inhibition of tissue uptake of amiodarone might have an important role in the preventative effect of antioxidants against amiodarone toxicity.
authors.affiliation: School of Medicine, Semmelweis University, Szentkirályi u. 46, 1088 Budapest, Hungary.
authors.forename: Márta
authors.initials: M
authors.lastname: Agoston
authors.forename: Ferenc
authors.initials: F
authors.lastname: Orsi
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Fehér
authors.forename: Krisztina
authors.initials: K
authors.lastname: Hagymási
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Orosz
authors.forename: Anna
authors.initials: A
authors.lastname: Blázovics
authors.forename: János
authors.initials: J
authors.lastname: Fehér
authors.forename: András
authors.initials: A
authors.lastname: Vereckei
mesh_terms: D000638:Amiodarone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism / Q000517:prevention & control*; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D010743:Phospholipids / Q000097:blood / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D012838:Silymarin / Q000494:pharmacology*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D010743:Phospholipids; D012838:Silymarin; D017392:Thiobarbituric Acid Reactive Substances; D014810:Vitamin E; C036116:desethylamiodarone; D000638:Amiodarone