Evaluation of amiodarone free radical toxicity in rat hepatocytes.
The possible roles of free radicals and lipid peroxidation in the mechanism of toxicity of amiodarone (AD) [2-butyl-3-(3',5'-diiodo-4' alpha-diethylaminoethoxybenzoyl)benzofuran] and its principle metabolite, desethylamiodarone (DE), were examined in primary cultured Sprague-Dawley male rat hepatocytes. AD (20 and 40 micrograms/ml) and DE (10 and 25 micrograms/ml) killed hepatocytes in concentration- and time-dependent fashions. Several antioxidants [Cu,Zn-superoxide dismutase (200 U/ml), catalase (200 U/ml), N,N'-diphenylphenylenediamine (DPPD; 25 microM), butylated hydroxytoluene (0.1 mM), and N-acetylcysteine (5 mM)] were incapable of preventing AD and DE hepatocyte toxicity. Only vitamin E (VE, d,l-alpha-tocopherol acetate; 20-200 microM) prevented AD and DE toxicity. No correlation between the onset of hepatocyte death by AD and DE and hepatocyte lipid peroxidation was seen. Both drugs inhibited NADPH-dependent rat liver microsomal superoxide production. These results, excluding the preventive effects of VE, do not support a free radical/lipid peroxidation mechanism of hepatocyte toxicity by AD and DE. VE may have prevented hepatocyte toxicity through non-antioxidant effects.
Ruch
R J
RJ
Department of Pathology, Medical College of Ohio, Toledo 43614.
Bandyopadhyay
S
S
Somani
P
P
Klaunig
J E
JE
D000111:Acetylcysteine / Q000494:pharmacology; D000638:Amiodarone / Q000031:analogs & derivatives / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002084:Butylated Hydroxytoluene / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005069:Evaluation Studies as Topic; D005609:Free Radicals; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008297:Male; D010655:Phenylenediamines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013482:Superoxide Dismutase / Q000494:pharmacology; D013997:Time Factors
D000975:Antioxidants; D005609:Free Radicals; D010655:Phenylenediamines; D002084:Butylated Hydroxytoluene; C004845:N,N'-diphenyl-4-phenylenediamine; D002374:Catalase; D013482:Superoxide Dismutase; C036116:desethylamiodarone; D000638:Amiodarone; D000111:Acetylcysteine