Salicylic acid-induced hepatotoxicity triggered by oxidative stress.
Salicylic acid is a widely used nonsteroidal anti-inflammatory drug (NSAID). But it is known to cause serious liver damage occasionally. Mitochondrial dysfunction and oxidative stress are predicted to be the major factors of salicylic acid-induced liver injury. We investigated the influence of salicylic acid on ATP contents, oxygen consumption and lipid peroxidation in the presence of the same concentration of salicylic acid. Leakage of lactate dehydrogenase (LDH) was significantly higher in the presence of 5mM salicylic acid than in its absence. Salicylic acid-induced thiobarbituric acid-reactive substance (TBARS) formation and spontaneous chemiluminescence (CL) in rat hepatocytes, whereas antioxidants, such as promethazine (PMZ) and N,N-diphenylphenylenediamine (DPPD), suppressed both TBARS formation and LDH leakage. TBARS formation in rat liver microsomes was suppressed by diethyldithiocarbamate (a specific inhibitor of cytochrome P450 (CYP)2E1) and diclofenac (a specific inhibitor of CYP2C11). These results suggest that salicylic acid-induced lipid peroxidation was related to oxidative metabolism mediated by CYP2E1 and CYP2C11. On the other hand, 5mM salicylic acid induced a drastic decrease of ATP contents in rat isolated hepatocytes. Furthermore, mitochondrial respiration control ratio (RC ratio), calculated by State 3/State 4 also decreased with the increase of salicylic acid concentration. These findings suggest that salicylic acid would trigger mitochondrial dysfunction and cause ATP decrease, leading to lethal liver cell injury by lipid peroxidation, although this hypothesis remains to be elucidated in vivo.
Doi
Hirokazu
H
Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.
Horie
Toshiharu
T
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D022781:Hepatocytes / Q000378:metabolism; D045022:Lactate Dehydrogenases / Q000378:metabolism; D015227:Lipid Peroxidation; D049449:Luminescence; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D010655:Phenylenediamines / Q000494:pharmacology; D011398:Promethazine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020156:Salicylic Acid / Q000633:toxicity*; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010655:Phenylenediamines; D017392:Thiobarbituric Acid Reactive Substances; D000255:Adenosine Triphosphate; C004845:N,N'-diphenyl-4-phenylenediamine; D045022:Lactate Dehydrogenases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D011398:Promethazine; D020156:Salicylic Acid