Cocaine-induced hepatotoxicity: lipid peroxidation as a possible mechanism.
In vitro experiments with hepatic washed microsomal preparations showed that malondialdehyde (MDA) formation was increased in a time- and concentration-dependent manner using COC or NC as the substrate. Though 1 mM COC or NC inhibited MDA formation, significant elevations were observed for 100, 10 or 1 microM concentrations. NC at 10 microM after a 30 minute incubation produced a 34% decrease in hepatic microsomal cytochrome P450 whereas 1 mM NC had no such effect. MDA formation in vivo, measured as total absorbance at 535 nm per gram liver, was found to be maximal 4 hours after 40 mg/kg NC ip. Elevations of serum transaminase (SGPT) however were not found until 6 hours after NC. We conclude from these studies that COC and NC induce lipid peroxidation in the liver of PB-pretreated Swiss-origin mice and that peroxidative attack may be a mechanism for hepatotoxicity of these compounds.
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology
D008054:Lipid Peroxides; C008671:norcocaine; D008315:Malondialdehyde; C036718:8-hydroxynorcocaine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D000410:Alanine Transaminase; D003042:Cocaine; D010634:Phenobarbital