Hepatic periportal necrosis induced by chronic administration of cocaine☆
Abstract
Cocaine was administered intraperitoneally to male mice at doses of 10, 20 or 30 mg/kg daily for 5 days for periods of 1, 2 and 3 weeks. A dose- and time-dependent periportal hepatic necrosis was noted. The extent of hepatic damage varied from vacuolization of hepatocytes to frank necrosis. No drug-related deaths were noted at any of the dosages studied. The hepatic damage elicited by chronic cocaine was found to be of a transient nature. Chronic cocaine treatment elevated serum glutamicpyruvic transminase levels in a dose- and time-dependent manner. Hepatic cytochrome P450 levels were depressed significantly in the 30 mg · kg−1 · day−1 dosage group at 1, 2 and 3 weeks. Hexobarbital-induced narcosis was lengthened significantly in the 30 mg · kg−1 · day−1 group throughout the course of the study. Chronic administration of cocaine produced a hepatic necrosis that closely resembled that produced by cocaine administered to animals pretreated with stimulators of hepatic metabolism.
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Cited by (42)
Modification of hepatic cytochrome P450 profile by cocaine-induced hepatotoxicity in DBA/2 mouse
1994, European Journal of Pharmacology: Environmental Toxicology andPrevious studies in our laboratory have shown that a hepatotoxic dose of cocaine increases coumarin 7-hydroxylase activity in male DBA/2 mouse liver. In the present study, the dose- and time-dependent responses of the hepatic CYP2A4/5 complex to cocaine-induced liver damage were studied. Cocaine increased CYP2A4/5 levels in a dose-dependent manner. The maximal increases in coumarin 7-hydroxylase activity (4-fold), microsomal CYP2A4/5 content (3-fold) and steady-state mRNA levels (10-fold) were observed at 24 h after administration of a single dose of 60 mg/kg cocaine coinciding with morphologically detectable diffuse liver damage, while the total P450 content was not changed. 3 and 5 days after the daily administration of cocaine severe, mainly pericentral (zone III of Rappaport), liver damage was apparent in parallel with a clear decline in CYP2A4/5 mRNA, protein content and coumarin 7-hydroxylase activity. After 5 days of treatment, CYP2A5 still remained at a very low level but an induction in CYP2B10 protein and related pentoxyresorufin O-dealkylase activity was observed. No marked changes in microsomal CYP2Cx and CYP1A1/2 contents or associated activities were observed. Dimethylnitrosamine N-demethylase activity, a marker for CYP2E1, decreased in parallel with increased cocaine dose and time and the severity of liver damage. Our results demonstrate that (i) administration of cocaine causes a clear but transient increase in the expression of Cyp2a-4/5 gene complex prior to overt liver damage and (ii) microsomal CYP2B10 and related 7-pentoxyresorufin O-dealkylase activity is markedly increased in animals treated for 5 days with cocaine concomitantly with the decrease in other monooxygenases indicating an association of coumarin 7-hydroxylase activity with liver injury and different roles for coumarin 7-hydroxylase and 7-pentoxyresorufin O-dealkylase activities in cocaine hepatotoxicity.
Hepatotoxicity is not increased in alcoholics with positive urinary cocaine metabolites
1994, Drug and Alcohol DependenceCocaine hepatotoxicity in mice has been reported by numerous investigators. Such hepatotoxicity in other animal models has been more difficult to produce. We prospectively assessed 1212 alcoholics admitted for detoxification for historical, clinical and laboratory evidence of concomitant cocaine/crack use and evidence of liver disease. The 470 cocaine positive subjects had both longer durations and higher average daily costs of cocaine/crack use than the 742 cocaine negative subjects, but had a shorter duration of alcohol use. Serum transaminases were higher in the cocaine negative group. There were no clinically severe cases of liver disease or rhabdomyolysis in either group. Serum hepatitis B surface antibody and hepatitis A antibody were more frequent in the cocaine positive subjects. In conclusion, in this large sample of alcoholics abusing cocaine, severe hepatotoxicity was not at all evident. The previous reports of hepatotoxicity may represent co-morbidity. Some possibilities include infection with a hepatitis or other virus, the presence of an adulterant, an idiosyncratic reaction or an enzymatic abnormality.
Enhancement of cocaine-induced hepatotoxicity by ethanol
1993, Drug and Alcohol DependenceThe contribution of moderate ethanol consumption on cocaine induced hepatotoxicity and the role lipid peroxidation plays as a possible mechanism of such increased hepatotoxicity were evaluated. Male C57BL/6 mice were injected interperitoneally (i.p.) with increasing doses of cocaine, from 10 to 50 mg/kg body weight daily and simultaneously fed a liquid diet containing 28% of the calories as ethanol for 5 or 9 weeks. Control mice received saline (i.p.) and an isocaloric carbohydrate diet. Lipid fluorescence and conjugated dienes of extracted lipids and amounts of malondialdehyde (MDA) were evaluated as indices of lipoperoxidation. In addition, serum alanine aminotransferase and aspartate transaminase were measured as indicators of liver injury and cellular death. After 9 weeks, ethanol consumption during cocaine treatment increased hepatic lipid fluorescence, conjugated dienes and MDA about twofold over mice treated with cocaine alone. Similarly, serum transaminases were 2.8–6-fold greater in mice consuming alcohol and treated with cocaine than in mice treated with cocaine only. Histological examination of livers from mice fed ethanol during treatment with cocaine exhibited increased hepatic injuries and necrosis. The data suggest that ethanol exacerbates cocaine-induced hepatotoxicity via increases in free radical activity and hepatic lipid peroxidation.
Potentiation of cocaine hepatotoxicity in human hepatocytes by ethanol
1992, Toxicology in VitroThe cytotoxic effect of cocaine on human hepatocytes was evaluated after 24 hr of exposure to cocaine by measuring the leakage of intracellular lactate dehydrogenase and the reduction of MTT. According to these endpoint parameters, the half-maximal cytotoxic concentration (IC50) of cocaine was 6.8 and 7.8 mm, respectively. Lower concentrations of cocaine, however, impaired basic metabolic functions of human hepatocytes. Exposure of cells to 2 mm-cocaine resulted in a 50% decrease in hepatic glycogen, a 40% decrease in cellular glutathione content and a 40% decrease in urea synthesis with respect to control values. Ethanol greatly potentiated cocaine-induced hepatotoxicity. After a 48-hr pretreatment of human hepatocytes with 50 mm-ethanol, concentrations of cocaine (0.25 mm) that had no effects on hepatocyte metabolism in the absence of ethanol, caused a 20% inhibition of the urea synthesis rate, a 40% depletion of glycogen stores and a 30% reduction in glutathione content. The results of our work show that ethanol significantly increases the toxic effects of cocaine on human hepatocytes.
Hepatic dysfunction accompanying acute cocaine intoxication
1991, Journal of HepatologyWe identified 39 patients with acute cocaine intoxication and rhabdomyolysis over an 8-year period. Twenty-three of the patients (59%) demonstrated biochemical evidence for hepatic dysfunction. Sixteen of these patients had severe liver injury as defined by an alanine aminotransferase (ALT) of > 400 U/l (group A). Seven had an ALT between 36–399 U/l (group B) and 16 showed no evidence of liver injury (group C). In contrast to those with normal ALT, the clinical course of the group A patients was more often accompanied by profound hypotension (44 vs. 0%, p < 0.025), disseminated intravascular coagulation (50 vs. 0%, p < 0.005), hyperpyrexia (75 vs. 25%, p < 0.025) and acute renal failure (81 vs. 0%, p < 0.001). Seven of the group A patients expired (44%). Histologic examination of liver tissue obtained from post-mortem samples demonstrated extensive centrilobular and midzonal necrosis in three cases and panlobular necrosis in two others. A mild lymphocytic infiltrate with bile duct proliferation was present in each specimen. We conclude that cocaine intoxication can be accompanied by liver dysfunction which is most likely multifactorial; the presence of severe dysfunction identifies a patient with potentially significant morbidity and mortality.
Cocaine and the liver
1991, Journal of Hepatology
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Supported by USPHS Grants GM15431 and GM00058.