Cocaine-induced hepatotoxicity

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Title Cocaine-induced hepatotoxicity
Publication Type dissertation
School or College College of Pharmacy
Department Pharmacology & Toxicology
Author Jordan, Ronald Arlie
Contributor Chinn, Denis; Kopiac, Larry
Date 1979-06
Description Cocaine treatment caused a dose-related decrease in the microsomal monooxygenase and conjugative activities at one day following administration, with progressive recovery of the activities over five days. Liver pathology showed midzonal necrosis with subsequent hepatocyte regeneration and resolution of necrotic areas. Serum glutamate-pyruvate transaminase activities were dramatically elevated in the early stages of toxicity. Norcocaine, an oxidative metabolite of cocaine, but not benzoyl-ecgonine, a hydrolytic metabolite, produced a pattern of hepa-totoxicity similar to cocaine. Both SKF 525-A and cobaltous chloride pretreatment decreased the hepatotoxic changes caused by cocaine and norcocaine. Phenobarbital pretreatment decreased the depression of monooxygenase activity with no effect on the increase in SGPT activity. Norcocaine-induced liver necrosis shifted from midzonal to periportal areas after phenobarbital-pretreatment of the animals. Pretreatment with 3-methylcholan-threne did not alter the midzonal necrosis caused by cocaine and norcocaine nor did it affect the changes in monooxygenase, conjugative, and SGPT activities. Both cocaine and norcocaine treatment produced a dose-dependent decrease in hepatic glutathione concentration. Diethyl maleate pretreatment potentiated the cocaine- and norcocaine-induced changes in enzyme parameters, while cysteine pretreatment decreased the changes. It was concluded that both cocaine and norcocaine are oxidatively metabolized to a reactive metabolite, and glutathione conjugation may be an important pathway in detoxifying the metabolite. The possible relationship between cocaine metabolism and cocaine- and norcocaine-induced hepatotoxicity was investigated in rats and mice. The microsomal enzyme systems from both untreated rats and mice were capable of metabolizing cocaine to oxidative and hydrolytic products. The pattern of in vitro me-tabolism of the two species showed quantitative rather than qualitative differences. Benzoylecgonine, a hydrolytic metabolite, was formed in greater amounts in rats than in mice, while norcocaine, an oxidative metabolite, was produced in approximately equal quantities. The total percent of cocaine metabolized was only slightly greater in rats than mice because the latterpro-duced greater quantities of unidentified metabolites. Rats pre-treated with diethyl maleate developed cocaine- and norcocaine-induced hepatotoxicity based on liver pathology and changes in the microsomal monooxygenase, conjugative, and serum glutamate-pyruvate transaminase activities. It was concluded that even though both rats and mice can oxidatively metabolize cocaine and norcocaine to a hepatotoxic reactive intermediate, rats do not normally demonstrate toxicity because of a more favorable ratio of glutathione related detoxication relative to activation.
Type Text
Publisher University of Utah
Subject Cocaine - Toxicology; Liver - Glycogenic function; Liver - Necrosis
Subject MESH Cocaine; Chemical and Drug Induced Liver Injury; Metabolic Detoxication, Phase I; Metabolic Detoxication, Phase II; Metabolic Clearance Rate
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital reproduction of Cocaine-Induced Hepatotoxicity. Print version available at J. Willard Marriott Library Special Collections, RC 39.5 1979 J67.
Rights Management Copyright © Ronald Arlie Jordan 1979
Format application/pdf
Format Medium application/pdf
Identifier us-etd2,197
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Funding/Fellowship Utah Research Committee Grant and the United States Public Health Service Grant No. GM 07265.
ARK ark:/87278/s6tb1nd1
Setname ir_etd
ID 192481
Reference URL https://collections.lib.utah.edu/ark:/87278/s6tb1nd1
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