Modulation of cocaine metabolism in primary rat hepatocyte cultures: Effects on irreversible binding and protein biosynthesis

Bouis, Patrick; Boelsterli, Urs A.

doi:10.1016/0041-008x(90)90165-q

Cited by 44 publications

(16 citation statements)

References 28 publications

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“…N-demethylation to norcocaine (NC) is the first step in the bioactivation of COC followed by formation of N-hydroxynorcocaine, and norcocaine nitroxide [261]. The toxicity of the drug is the result of further oxidative metabolism, either through redox cycling between N-hydroxynorcocaine and norcocaine nitroxide leading to NADPH depletion as well as the generation of superoxide anion (O2 z 2 ) and H2O2, or the production of a still to be identified reactive metabolite, derived from cocaine nitroxide and norcocaine nitrosonium [234,252,259,264]. Recent evidence suggests that the production of ROS plays an important role in acute cocaine hepatotoxicity, both in vitro [234,246,259,262] and in vivo [265], and uncoupling of both P450-mediated monooxygenase activity [262] and mitochondrial respiration [246,266] have been hypothesized as possible sources of ROS following cocaine administration.…”

Section: Cocaine Mediated Hepatotoxicity (Cmh)mentioning

confidence: 99%

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Side Effects of Cocaine Abuse: Multiorgan Toxicity and Pathological Consequences

Riezzo

Fiore²,

Carlo³

et al. 2012

CMC

178

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Cocaine is a powerful stimulant of the sympathetic nervous system by inhibiting catecholamine reuptake, stimulating central sympathetic outflow, and increasing the sensitivity of adrenergic nerve endings to norepinephrine (NE). It is known, from numerous studies, that cocaine causes irreversible structural changes on the brain, heart, lung and other organs such as liver and kidney and there are many mechanisms involved in the genesis of these damages. Some effects are determined by the overstimulation of the adrenergic system. Most of the direct toxic effects are mediated by oxidative stress and by mitochondrial dysfunction produced during the metabolism of noradrenaline or during the metabolism of norcocaina, as in cocaine-induced hepathotoxicity. Cocaine is responsible for the coronary arteries vasoconstriction, atherosclerotic phenomena and thrombus formation. In this way, cocaine favors the myocardial infarction. While the arrhythmogenic effect of cocaine is mediated by the action on potassium channel (blocking), calcium channels (enhances the function) and inhibiting the flow of sodium during depolarization. Moreover chronic cocaine use is associated with myocarditis, ventricular hypertrophy, dilated cardiomyopathy and heart failure. A variety of respiratory problems temporally associated with crack inhalation have been reported. Cocaine may cause changes in the respiratory tract as a result of its pharmacologic effects exerted either locally or systemically, its method of administration (smoking, sniffing, injecting), or its alteration of central nervous system neuroregulation of pulmonary function. Renal failure resulting from cocaine abuse has been also well documented. A lot of studies demonstrated a high incidence of congenital cardiovascular and brain malformations in offspring born to mothers with a history of cocaine abuse.

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Section: Cocaine Mediated Hepatotoxicity (Cmh)mentioning

confidence: 99%

“…However, it has been proposed that norcocaine nitroxide, can be further metabolized by undergoing a one-electron oxidation to a nitrosonium ion that binds to critical subcellular targets [264,277].…”

Section: Cocaine Mediated Hepatotoxicity (Cmh)mentioning

confidence: 99%

Side Effects of Cocaine Abuse: Multiorgan Toxicity and Pathological Consequences

Riezzo

Fiore²,

Carlo³

et al. 2012

CMC

178

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“…The observation in our study of the buildup of lipids, the dilation of cistemae of RER containing osmiophilic globules, and the loss of membrane-bound ribosomes suggests that protein synthesis and transport may be disrupted in cocainetreated hepatocytes. Inhibition of protein synthesis has been reported to occur in isolated rat hepatocytes after cocaine administration (7).…”

Section: Discussionmentioning

confidence: 99%

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

1992

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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.

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“…This metabolite is believed to bind to critical target proteins in the hepatic tissue, and, based on comparative electrochemical in vitro studies, to induce hemolysis of red blood cells [54,55]. In agreement with this hypothesis, Bouis and Boelsterli (1990) demonstrated the formation of a reactive cocaine metabolite that irreversibly binds to cellular protein in the liver, and its association with impairment of hepatocellular function, through in vivo and in vitro modulation of the rate of oxidative cocaine metabolism in rats [56].…”

Section: -mentioning

confidence: 74%

Contribution of Oxidative Metabolism to Cocaine-Induced Liver and Kidney Damage

Valente

Carvalho²,

Bastos³

et al. 2012

CMC

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Cocaine is a potent psychoactive illicit substance and its abuse represents a major health burden worldwide. The pharmacodynamics and toxicity of cocaine have been extensively documented, and are generally associated to its affinity towards neurotransmitters transporters and several receptors. However, drug-related formation of reactive compounds, as is the case of pro-oxidant reactive species, and interaction at molecular level is still an understudied matter. The involvement of oxidative stress (OS) in cocaine-induced toxicity has been reported in both human and animal models, in several organs and systems, including heart, liver, kidney, and central nervous system (CNS). Cytochrome P450 (CYP450)-mediated cocaine metabolism yields the reactive pro-oxidant compound norcocaine (NCOC) and further oxidative metabolites. Special emphasis should be given to the stable radical norcocaine nitroxide (NCOC-NO·), which plays a key role in cocaine-induced hepatotoxicity, either by entering a futile redox cycle with an N-oxidative metabolite, or by being further oxidized to a highly reactive ion. In fact, cocaine-induced generation of reactive oxygen species (ROS) and consequent OS has been postulated based on the reactivity of cocaine N-oxidative metabolites. Depletion of cellular antioxidant defenses and impairment of mitochondrial respiration have also been considered important causes of ROS production, and subsequent cell death mediated by cocaine. The present review provides a thorough description of the current knowledge on cocaine oxidative metabolism and its role on drug-induced liver and kidney damage.

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Modulation of cocaine metabolism in primary rat hepatocyte cultures: Effects on irreversible binding and protein biosynthesis

Cited by 44 publications

References 28 publications

Side Effects of Cocaine Abuse: Multiorgan Toxicity and Pathological Consequences

Side Effects of Cocaine Abuse: Multiorgan Toxicity and Pathological Consequences

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

Contribution of Oxidative Metabolism to Cocaine-Induced Liver and Kidney Damage

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