Toxicity of ethacrynic acid in isolated rat hepatocytes.
Ethacrynic acid, a loop diuretic drug, caused lipid peroxidation in isolated rat hepatocytes. The thiobarbituric acid reactive substances (TBARS) formation showed a good correlation with the leakage of glutamic-oxaloacetic acid transaminase (GOT) from the hepatocytes. The addition of antioxidants such as N, N'-diphenyl-p-phenylenediamine (DPPD) and promethazine to the isolated rat hepatocyte suspension containing ethacrynic acid prevented the lipid peroxidation and decreased the GOT leakage to some extent. SKF-525A inhibited the oxidative metabolism of ethacrynic acid and decreased the TBARS formation, suggesting that the lipid peroxidation was caused by the oxidative metabolism. The intracellular reduced glutathione markedly decreased in the hepatocyte suspension containing ethacrynic acid and the hepatocellular protein sulfhydryls were decreased, which was negatively correlated with the GOT leakage. Thus the ethacrynic acid-induced hepatotoxicity was found to be related to the lipid peroxidation and the decrease of cellular protein sulfhydryls.
Yamamoto
K
K
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan.
Masubuchi
Y
Y
Narimatsu
S
S
Kobayashi
S
S
Horie
T
T
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004232:Diuretics / Q000633:toxicity*; D004336:Drug Antagonism; D004976:Ethacrynic Acid / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D015227:Lipid Peroxidation; D008297:Male; D010655:Phenylenediamines / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D011398:Promethazine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000032:analysis / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000975:Antioxidants; D004232:Diuretics; D010655:Phenylenediamines; D013438:Sulfhydryl Compounds; D017392:Thiobarbituric Acid Reactive Substances; D011335:Proadifen; C004845:N,N'-diphenyl-4-phenylenediamine; D001219:Aspartate Aminotransferases; D011398:Promethazine; D004976:Ethacrynic Acid