N-acetylcysteine pretreatment decreases cocaine and endotoxin-induced hepatotoxicity.
Cocaine produces hepatotoxicity by a mechanism that remains undefined but has been linked to its oxidative metabolism. Endotoxin (lipopolysaccharide, LPS) is also a well-known cause of hepatic damage, and exposure to noninjurious doses of LPS increases the toxicity of certain hepatotoxins. Previously it was demonstrated that exposure to noninjurious doses of LPS dramatically increases cocaine-mediated hepatotoxicity (CMH). This study was conducted to investigate whether pretreatment with N-acetylcysteine (NAC), a glutathione (GSH) precursor and an antioxidant agent, inhibits LPS potentiation of CMH. For 5 consecutive days, male CF-1 mice were administered daily oral NAC (200 mg/kg) or sterile saline followed an hour later by cocaine (20 mg/kg) or sterile saline. Four hours following the last cocaine or saline treatment, the mice were administered 12 x 10(6) EU LPS/kg or sterile saline. For the cocaine alone and cocaine and LPS groups, NAC pretreatment significantly decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities with absence of necrotic hepatic lesions, indicating a reduction of liver injury. In addition, in all groups pretreated with NAC, hepatic GSH concentration was significantly increased, as were hepatic and blood glutathione peroxidase (GPx) and catalase (CAT) activities. In conclusion, the results demonstrate that NAC pretreatment exerted a protective effect against LPS potentia-tion of CMH.
Labib
Ramez
R
Department of Pharmacology and Physiology, New Jersey Medical School, Newark, New Jersey 07103-2714, USA.
Abdel-Rahman
Mohamed S
MS
Turkall
Rita
R
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D004731:Endotoxins / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction
D004731:Endotoxins; D008070:Lipopolysaccharides; D003042:Cocaine; D000111:Acetylcysteine