Liver damage from cocaine in mice

doi:10.1016/0024-3205(77)90291-0

Life Sciences

Volume 20, Issue 6, 15 March 1977, Pages 1035-1041

https://doi.org/10.1016/0024-3205(77)90291-0 Get rights and content

Abstract

Four daily injections of 20 mg per kg cocaine hydrochloride into B6AF₁/J mice produced focal necrosis of liver parenchymal cells in the midzonal region. Massive liver damage and marked elevation of serum glutamic-oxaloacetic transaminase was observed after a single injection of 50 mg per kg cocaine-HC1. This damage led to increased sleep time after pentobarbital, and a decreased rate of pentobarbital metabolism $in vivo$ .

References (11)

E. Farber
Gastroenterology
(1966)
L. Shuster
Neuroscience Abstracts
(1976)
A. Karmen
J. Clin. Invest.
(1955)
L. Shuster et al.
J. Med. Education
(1965)
A. Goldstein
Biostatistics
(1964)

There are more references available in the full text version of this article.

Cited by (84)

Effects of anti-cocaine vaccine and viral gene transfer of cocaine hydrolase in mice on cocaine toxicity including motor strength and liver damage
2013, Chemico-Biological Interactions
Citation Excerpt :
As the equilibrium shifts, drug will off-load from the antibody to be destroyed in turn, restoring the original state. Thus, these agents might act synergistically to shield the brain (reducing addiction liability) and also protect peripheral tissues, such as liver, that are direct targets of cocaine toxicity [5–7]. We recently presented supportive behavioral evidence for this idea [8].
In developing an vivo drug-interception therapy to treat cocaine abuse and hinder relapse into drug seeking provoked by re-encounter with cocaine, two promising agents are: (1) a cocaine hydrolase enzyme (CocH) derived from human butyrylcholinesterase and delivered by gene transfer; (2) an anti-cocaine antibody elicited by vaccination. Recent behavioral experiments showed that antibody and enzyme work in a complementary fashion to reduce cocaine-stimulated locomotor activity in rats and mice. Our present goal was to test protection against liver damage and muscle weakness in mice challenged with massive doses of cocaine at or near the LD50 level (100–120 mg/kg, i.p.). We found that, when the interceptor proteins were combined at doses that were only modestly protective in isolation (enzyme, 1 mg/kg; antibody, 8 mg/kg), they provided complete protection of liver tissue and motor function. When the enzyme levels were ∼400-fold higher, after in vivo transduction by adeno-associated viral vector, similar protection was observed from CocH alone.
Lipidomic profiling reveals protective function of fatty acid oxidation in cocaine-induced hepatotoxicity
2012, Journal of Lipid Research
During cocaine-induced hepatotoxicity, lipid accumulation occurs prior to necrotic cell death in the liver. However, the exact influences of cocaine on the homeostasis of lipid metabolism remain largely unknown. In this study, the progression of subacute hepatotoxicity, including centrilobular necrosis in the liver and elevation of transaminase activity in serum, was observed in a three-day cocaine treatment, accompanying the disruption of triacylglycerol (TAG) turnover. Serum TAG level increased on day 1 of cocaine treatment but remained unchanged afterwards. In contrast, hepatic TAG level was elevated continuously during three days of cocaine treatment and was better correlated with the development of hepatotoxicity. Lipidomic analyses of serum and liver samples revealed time-dependent separation of the control and cocaine-treated mice in multivariate models, which was due to the accumulation of long-chain acylcarnitines together with the disturbances of many bioactive phospholipid species in the cocaine-treated mice. An in vitro function assay confirmed the progressive inhibition of mitochondrial fatty acid oxidation after the cocaine treatment. Cotreatment of fenofibrate significantly increased the expression of peroxisome proliferator-activated receptor α (PPARα)-targeted genes and the mitochondrial fatty acid oxidation activity in the cocaine-treated mice, resulting in the inhibition of cocaine-induced acylcarnitine accumulation and other hepatotoxic effects. Overall, the results from this lipidomics-guided study revealed that the inhibition of fatty acid oxidation plays an important role in cocaine-induced liver injury.
Inflammation and Hepatotoxicity
2010, Comprehensive Toxicology, Second Edition
Inflammatory episodes are common in people and animals and usually serve a protective role against invading microorganisms, disease, and tissue injury. Under some conditions, however, inflammation can precipitate tissue injury or can modify susceptibility to toxicity from concurrent exposure to xenobiotic agents. This chapter includes an introduction to the critical components of inflammatory responses, including types of cells, numerous soluble mediators, the hemostatic and complement systems, and alterations in gene expression. The role of inflammation in mediating the hepatotoxic effects of, or altering the sensitivity to, certain xenobiotic agents is reviewed.
Gender differences in cocaine pharmacokinetics in CF-1 mice
2005, Toxicology Letters
Hepatocellular damage is thought to occur as a result of cytochrome P450-mediated oxidation of cocaine to norcocaine (NC), a precursor of the hepatotoxic nitrosonium ion. However, this damage occurs only in male mice, with females exhibiting minimal biochemical and histological signs of hepatocellular stress. The objective of this study was to determine the plasma time course and tissue disposition of cocaine and its metabolites to further investigate the role that metabolism may play in the gender difference observed. Male and female CF-1 mice were orally administered 20 mg/kg cocaine hydrochloride once daily for 7 days. Blood samples were withdrawn at various time points post-injection and analyzed for cocaine and its metabolites benzoylecgonine (BE), norcocaine, ecgonine methyl ester (EME), and ecgonine (E). In addition, tissue concentrations of cocaine and its metabolites were determined in liver, heart, brain, and kidney tissue. The results demonstrated that the plasma elimination half-life of cocaine is nearly three times longer in males versus females. Non-hepatotoxic hydrolysis metabolites BE, EME, and E were higher in female tissues while norcocaine was detected in tissues of male animals only. This study revealed that differences in cocaine pharmacokinetics and the resultant differences in the biodisposition of cocaine and its metabolites in tissues contribute to the mechanism of gender difference seen in cocaine hepatotoxicity.
Adverse hepatic drug reactions: Inflammatory episodes as consequence and contributor
2004, Chemico-Biological Interactions
Citation Excerpt :
It has been used as a local anesthetic, but its notoriety arises from its use as a recreational drug. Hepatotoxicity associated with chronic cocaine use occurs in humans [70,71], and experimental models in animals have been developed [72,73]. In people, there is no consistent zonal specificity to cocaine-induced liver injury; damage occurs in either centrilobular or periportal regions [70,74].
Susceptibility to drug toxicity is influenced by a variety of factors, both genetic and environmental. The focus of this article is the evidence addressing the hypothesis that inflammation is both a result of and a susceptibility factor for drug toxicity, with an emphasis on liver as a target organ. Results of studies suggesting a role for inflammatory mediators in the hepatotoxicity caused by acetaminophen or ethanol are discussed. For several drugs, the evidence from animal models that concurrent inflammation increases injury is presented. In addition, the occurrence of adverse drug reactions in people with preexisting inflammatory diseases is considered. The special case of idiosyncratic drug reactions is discussed and the potential raised for development of animal models for this type of drug toxicity. The conclusion is that inflammatory factors should be considered as determinants of sensitivity to adverse drug reactions.
Cocaine-protein targets in mouse liver
2003, Biochemical Pharmacology
Citation Excerpt :
In some cases, hepatic injury from cocaine is prominent [4–8], occasionally leading to hepatic failure and death. Consistent with these case reports, administration of cocaine to laboratory animals has been shown to produce severe hepatocellular necrosis [9,10]. The mechanism of cocaine hepatotoxicity is not well understood, although it is clear from studies in mice that N-oxidative metabolism of cocaine is required for this effect [11].
Cocaine has been shown to be hepatotoxic in mice, rats and humans. N-Oxidative metabolism of cocaine is required for this effect, and it has been proposed that binding of cocaine reactive metabolites formed via this pathway might be responsible for cytotoxicity. To explore this hypothesis, cocaine–protein adducts in liver following cocaine treatment in naive ICR mice were examined by Western blot analysis and compared with those formed in mice pretreated with phenobarbital or β-naphthoflavone. Phenobarbital and β-naphthoflavone pretreatments have been shown previously to shift the hepatic necrosis in ICR mice from the midzonal region to periportal and perivenular regions, respectively. Similar patterns of cocaine–protein adduction were detected in naive, phenobarbital-pretreated and β-naphthoflavone-pretreated mice, however, suggesting a consistent set of target proteins regardless where within the lobule toxicity occurs. To confirm that Western blot analysis using anti-cocaine antibody was capable of detecting all of the major cocaine–protein adducts, a separate experiment was conducted in which mice were treated with $^{14} C$ -labeled cocaine and cocaine–protein adducts were detected fluorographically. This technique detected essentially the same protein adducts as the Western blots. Two of the protein adducts were isolated, subjected to N-terminal sequence analysis, and found to have homology with hsp 60 and transferrin. Western blot analysis using anti-hsp 60 and anti-transferrin antibodies following two-dimension PAGE separation was used to confirm the identity of these protein targets. Impairment of function of either protein could plausibly contribute to cocaine hepatotoxicity, although this remains to be demonstrated.

View all citing articles on Scopus

View full text

Liver damage from cocaine in mice

Abstract

Gastroenterology

Neuroscience Abstracts

J. Clin. Invest.

J. Med. Education

Biostatistics