Hepatic Morphologic and Biochemical Changes Induced by Subacute Cocaine Administration in Mice

Abstract

The initial event and site of cocaine-induced hepatic injury have not been elucidated. In an attempt to identify the minimal effective dose and the site of injury, we have examined the livers of mice exposed to small daily doses of cocaine, using morphological and biochemical methods. All doses of cocaine greater than 5 mg/kg were able to cause significant elevation of serum glutamic pyruvic transaminase. Light microscopy revealed a progression of centrilobular necrosis as the dose increased from 10-30 mg/kg. The initial morphologic changes observed prior to necrosis included aggregation of intermediate filaments and dilation of rough endoplasmic reticulum with loss of ribosomes. Immunohistochemistry, using antibodies to cytokeratins, showed staining of individual hepatocytes in livers from cocaine-treated animals but not in controls. In contrast to earlier reports, we found little, if any, disruption of mitochondria. In vitro, the direct application of cocaine, norcocaine, and N-hydroxynorcocaine on isolated mitochondria had no effect on the ADP:O or respiratory control ratios, at concentrations up to 2.0 mM. Our studies demonstrate that any early cellular alterations in cocaine-induced hepatic injury are manifested in intermediate filaments and endoplasmic reticulum with no evidence of mitochondrial involvement.

Subacute Cocaine Treatment Changes Expression of Mouse Liver Cytochrome P450 Isoforms

“…Unless otherwise specified, 16-18 h after the final drug administration animals were killed by cervical dislocation and the liver microsomes were prepared as described by Powers et al [17].…”

Characterization of cocaine-elicited cell vacuolation: the involvement of calcium/calmodulin in organelle deregulation

“…Cocaine has been shown to cause cardiovascular, central nervous and neuromuscular system toxicity, complications of renal and pulmonary injury, hapatotoxicity as well as genotoxicity [10][11][12]. In addition to its systematic toxicity, cocaine has also been known to affect morphology or functions of intracellular apparatus, including disturbance in spindle formation [13], perturbation of neurite extension [14], disruption of function and morphology of mitochondria [15], induction of ER dilation [16] and impairment of lysosomal proteolysis [17]. One of the most intriguing morphological alterations upon cocaine exposure is vacuole formation in the cytoplasm.…”

Characterization of Differential Cocaine Metabolism in Mouse and Rat through Metabolomics-Guided Metabolite Profiling

“…Many observed cytotoxic events in cocaine overdose, including covalent binding to proteins, glutathione depletion, and lipid peroxidation, have been defined as the direct consequences of forming these reactive metabolites (Evans, 1983;Kloss et al, 1983;Masini et al, 1997). The development of CIH is likely due to multiple downstream events, such as the disruption of normal function of mitochondria and other intracellular organelles, the dysregulation of signaling pathways in cell death and survival, and the necrosis and apoptosis of hepatocytes (Gottfried et al, 1986;Shuster et al, 1988;Powers et al, 1992). …”

“…Rodents, mainly mouse and rat, have been widely used for examining various pathophysiological effects of cocaine, including CIH (Lakoski et al, 1992). Compared with the cocaine-naïve rat, the cocaine-naïve mouse is generally much more vulnerable to CIH (Mehanny and AbdelRahman, 1991;Powers et al, 1992). Cocaine metabolism has been considered a major factor underlying the different susceptibility to CIH (Harbison et al, 1992).…”