Hepatic biochemical changes as a result of acute cocaine administration in the mouse.
The biochemical mechanism of cocaine hepatotoxicity is thought to involve enzymatic formation of reactive metabolites. The exact hepatocellular effects of these metabolites have yet to be established. This study was designed to monitor, in a time course after an acute cocaine dose, biochemical parameters that are important in cellular defense and homeostasis in vivo. The hepatic parameters measured were ATP as an indicator of cellular energetic status, reduced and oxidized glutathione, NADH and NADPH as measures of redox changes, and thiobarbituric acid-reactive products and microsomal conjugated dienes to determine the extent of lipid peroxidation. In addition, serum ALT levels were determined at each time point to assess the extent of toxicity. Inbred mouse strains selected for their relative sensitivity (male DBA/2Ibg) and resistance (male C57BL/6Ibg) to cocaine-mediated hepatotoxicity were used in this study. Animals were given an acute 50 mg/kg intraperitoneal dose of cocaine, and at various times after administration the hepatic and serum determinations were made. The results of this study confirm the strain difference in cocaine-induced hepatotoxicity and also indicate that there are changes in the biochemistry of the liver that are brought about by acute cocaine administration. In particular, depletions of hepatic GSH, NADH, NADPH and ATP coupled with significant increases in oxidized glutathione were observed in the DBA mouse. C57BL mice showed similar decreases in reduced glutathione, NADH and NADPH but exhibited no significant depletion of hepatic ATP. A similar extent of lipid peroxidation was seen in both mouse strains after cocaine administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Boyer
C S
CS
Molecular Toxicology and Environmental Health Sciences Program, University of Colorado Health Sciences Center, Denver 80309-0297.
Petersen
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DR
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D002940:Circadian Rhythm; D003042:Cocaine / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009249:NADP / Q000378:metabolism; D013997:Time Factors
D008054:Lipid Peroxides; D009249:NADP; D000410:Alanine Transaminase; D005978:Glutathione; D003042:Cocaine; D019803:Glutathione Disulfide