Cocaine hepatotoxicity

Macrovesicular steatosis can be attributed to alcohol or cocaine, but massive liver necrosis is more probably due to cocaine. The mechanisms of cocaine hepatotoxicity, such as increased lipid peroxidation, free radical activity, and impaired calcium sequestration, may be potentiated by alcohol. 

Cocaine hepatotoxicity Influence of hepatic enzyme inducing and inhibiting agents on the site of necrosis. Hepatology 15 934-940, 1992. 

In animals pretreated with ethanol, metabolism of cocaine to norcocaine and benzoylnorecgonine increased, as reflected by higher tissue AUCs, as compared with those receiving water. Ethanol pretreatment also resulted in measurable levels of norcocaethylene in liver and lung. These observations are consistent with the increased hepatotoxicity (presumably due to enhanced N-oxidative metabolism) observed when mice were exposed to cocaine or cocaethylene and the esterase inhibitor diazinon (Roberts et al. 1992 Thompson et al. 1979). This shift toward N-oxidative metabolism provides a mechanism to explain potentiation of cocaine hepatotoxicity by ethanol (lover et al. 1991). Detection of norcocaethylene in ethanol- pretreated rats is consistent with norcocaethylene detected in the hair of heavy cocaine users, suggesting common pathways including hydrolysis, transesterification, and N-demethylation (figure 1) (Cone etal. 1991). 

Jover, R. Ponsoda, X. Gomez-Lechon, M.J. Herrero, C. del Pino, J. and Castell, J.V. Potentiation of cocaine hepatotoxicity by ethanol in human hepatocytes. Toxicol Appl Pharmacol 107 526-534, 1991. 

Cocaine-mediated hepatotoxicity has been associated with the conversion of cocaine to norcocaine and further oxidation products. The enzymes involved in in vitro hepatic oxidative N-demethylation of cocaine (192) were investigated (237), and two different enzymatic pathways appear to be important in the formation of the hepatotoxic metabolite. Cytochrome P-450 monooxygenases accomplish the direct N-demethylation of cocaine to norcocaine (194) as confirmed by induction and inhibition studies (Scheme 42). The second pathway for cocaine N-demethylation involves formation of cocaine /V-oxide (193) as an intermediate and two enzymes. A flavin-containing monooxygenase is first thought to convert cocaine to cocaine /V-oxide, followed by cytochrome P-450-... 

Cocaine may be TV-demethyl ate d by the cytochrome P450 system to produce an active metabolite, norcocaine. Further breakdown produces A-hydroxynorcocaine and norcocaine nitroxide. Further metabolism produces a highly reactive free radical that is thought to be responsible for the hepatotoxicity observed in cocaine users.1... 

Acute hepatitis induced by intranasal cocaine, with transient increases in liver enzymes, has been reported in three HIV-positive patients (202). All had non-active chronic viral hepatitis with normal immunological status one was seropositive for hepatitis B virus and two were positive for hepatitis C virus. A few days after intranasal cocaine use, serum transaminases rose to high values, and two of the patients had fever, stiffness, sweats, and hepatomegaly. Alcohol and hepatotoxic agents were ruled out. Within a few days, the clinical and laboratory signs of hepatitis improved in all three cases. 

Hepatotoxicity secondary to cocaine exposure can be associated with hyperthermia, ischemia, or a direct cocaine effect. Another possible mechanism may be an acquired mitochondrial defect (203). 

Rahman TM, Wadsworth C, Anson G, Wendon J. Cocaine-induced hepatotoxicity or an acquired mitochondrial defect Clin Int Care 2004 15 61-3. 

Alkaloids that contain pyrrolidine and pyrrolizidine ring systems are derived from the nonprotein amino acid, L-ornithine. Cocaine (Nl) and (—)-hyoscyamine, the two important pyrrolidine alkaloids that contain a tropane ring system, have been found to occur in coca (Erythroxylon coca, Erythroxylaceae) leaves and the whole plant of the deadly nightshade (Atropa belladonna, Solanaceae). The hepatotoxic alkaloid senecionine (N2) contains a bicyclic pyrrolizidine skeleton derived from two molecules of L-ornithine. 

Cocaine abusers have reported that alcohol prolongs the euphoriant properties of cocaine, while ameliorating the acutely unpleasant physical and psychological sequelae, primarily paranoia and agitation. It may also lessen the dysphoria associated with acute cocaine abstinence. It has also been proposed that concurrent alcohol abuse may be an integral part of cocaine abuse. The combination of cocaine with alcohol can cause enhanced hepatotoxicity... 

Leikin JB, Krantz AJ, Zell-Kanter M, Barkin RL, and Hryhorczuk DO (1989) Clinical features and management of intoxication due to hallucinogenic drugs. Medical Toxicology and Adverse Drug Experience 4 324-350. Odeleye OE, Watson RR, and Eskelson CD (1993) Enhancement of cocaine-induced hepatotoxicity by ethanol. Drug and Alcohol Dependence 31 253-263. 

Van Thiel DH, Perper JA. Hepatotoxicity associated with cocaine abuse. Recent Dev Alcohol 1992 10 335-341. 

Oxidation is the second major process in degradation of cocaine, and it occurs in the liver as a result of activity of microsomal cytochrome P-450 enzymes. Oxidative reactions account for hydroxylation of the aromatic ring of the benzoic acid moiety and for N-demethylation [30, 42, 43]. Specifically, it appears to be the 3a form of P-450 that is responsible, since feeding inhibitors of this isoform to mice inhibited the hepatotoxicity caused by the demethylated product [44],... 

Stroescu and coworkers (1986) have reported the influence of the body s electrolyte composition on the toxic effect of morphine. In mice, depletion of body sodium ion increased the toxicity, which was found to decrease by sodium loading. Glutathione depletors such as cocaine, when coadministered with an opiate such as morphine or heroin, may enhance hepatotoxicity in humans (McCartney 1989). Such a potentiation effect has been explained by the authors as being a result of depletion of endogenous glutathione, which conjugates with morphine to prevent toxic interaction with hepatic cells. 

The hepatotoxicity of cocaine is known to be associated with its N-oxidative pathway. Cocaine is first hf-demethylated to norcocaine, followed by oxidation to N-hydroxynorcocaine and then to norcocaine nitroxide. Norcocaine nitroxide is the active metabolite. Rauckman et al. (1984) presented a scheme of nonooxygenase-catalyzed reduction of... 

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