Inhibition of cocaine oxidative metabolism attenuates endotoxin potentiation of cocaine mediated hepatotoxicity.
The oxidative metabolism of cocaine by the microsomal monooxygenase enzymes has been postulated to be essential for cocaine mediated hepatotoxicity (CMH). Endotoxin (lipopolysaccharide, LPS), a well-known cause of hepatic damage, previously has been demonstrated to dramatically increase CMH. The mechanism of this interaction has not been clearly elucidated, but cocaine oxidative metabolism appears to sensitize hepatocytes so that subsequent exposure to small amounts of LPS can further augment CMH. This study was conducted to investigate if dimethylaminoethyl-2,2-diphenylvalerate (SKF-525A) pretreatment inhibits LPS potentiation of CMH. For 5 consecutive days, male CF-1 mice were administered daily SKF-525A (50 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 sterile saline 12x10(6) EU LPS/kg, i.p. The mice were sacrificed 18 h later by decapitation. Pretreatment with SKF-525A reversed the hepatic injury caused by cocaine alone or cocaine and LPS treatments, as indicated by both histologic evaluation and serum alanine transaminase (ALT) and aspartate transaminase (AST) activities. In particular, SKF-525A completely reversed the effects of cocaine alone on liver and blood reduced gluthathione (GSH), glutathione peroxidase (GPx) and catalase (CAT) and hepatic glutathione reductase (GRx) activities. However, SKF-525A was ineffective against the effect of LPS alone on liver and blood GPx and CAT or on hepatic GSH and GRx, suggesting that these effects were not mediated by cytochrome P450 oxidative metabolism. The pattern of biochemical changes persisting with SKF-525A pretreatment in the LPS and cocaine group resembled those of the LPS alone group. The results suggest that cytochrome P450 oxidative metabolism of cocaine is largely responsible for CMH with potentiation by LPS achieved through a different mechanism involving oxidative stress.
Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103-2714, USA.
Ramez
R
Labib
Rita
R
Turkall
Mohamed S
MS
Abdel-Rahman
D000818:Animals; D001711:Biotransformation; D002374:Catalase / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology*; D003042:Cocaine / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D004731:Endotoxins / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D011335:Proadifen / Q000494:pharmacology
D004731:Endotoxins; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D011335:Proadifen; D002374:Catalase; D005979:Glutathione Peroxidase; D005978:Glutathione; D003042:Cocaine