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Cocaine-protein targets in mouse liver
Florence M Ndikum-Moffor1, Stephen M Roberts
1Center for Environmental and Human Toxicology, University of Florida, Box 110885, Gainesville, FL 32611, USA.
Biochemical Pharmacology
|June 24, 2003
Summary
Cocaine causes liver damage through reactive metabolites binding to proteins. Researchers identified heat shock protein 60 (hsp 60) and transferrin as key targets in mice, suggesting their dysfunction contributes to cocaine hepatotoxicity.
Area of Science:
- Toxicology
- Molecular Biology
- Biochemistry
Background:
- Cocaine is hepatotoxic in various species, including humans.
- N-oxidative metabolism of cocaine generates reactive metabolites.
- These metabolites may bind to liver proteins, causing cytotoxicity.
Purpose of the Study:
- To investigate the hypothesis that cocaine-reactive metabolite binding to proteins causes liver damage.
- To identify specific liver proteins that form adducts with cocaine metabolites.
Main Methods:
- Western blot analysis of liver protein adducts in naive and pretreated mice.
- Comparison of adduct patterns with known shifts in hepatic necrosis regions.
- Fluorographic detection of adducts using 14C-labeled cocaine.
- N-terminal sequencing and 2D PAGE-Western blot to identify protein targets.
Main Results:
- Similar cocaine-protein adduct patterns were observed across different mouse models.
- Western blot and fluorography detected consistent sets of protein adducts.
- Two major adducts were identified as heat shock protein 60 (hsp 60) and transferrin.
Conclusions:
- Cocaine-reactive metabolites bind to a consistent set of target proteins, including hsp 60 and transferrin.
- Impairment of hsp 60 or transferrin function may contribute to cocaine-induced liver injury.
- Further research is needed to confirm the functional impact of these protein adducts.