Persistent Link:
http://hdl.handle.net/10150/187813
Title:
CYSTAMINE TREATMENT OF CHEMICALLY-INDUCED HEPATOTOXICITY.
Author:
MACDONALD, JOHN ROBERT.
Issue Date:
1984
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
There are few examples of therapeutic treatments in chemically-induced toxicity compared to pretreatments that protect against chemical injury. Cystamine treatment 12 hours after carbon tetrachloride (CCl₄) was reported to have therapeutic effects on CCl₄-induced hepatic necrosis via an unknown mechanism. The objectives of this project were to develop. quantitative animal models to characterize cystamine treatment of chemically-induced hepatotoxicity and to use the models to investigate possible mechanisms of the therapeutic effect. Cystamine produced dose related therapeutic effects against both CCl₄ and galactosamine-induced hepatic necrosis in male Sprague-Dawley rats. The therapeutic effect on galactosamine-induced damage demonstrated that cystamine has therapeutic effects that are unrelated to inhibition of early biochemical events initiating damage. This was an important finding since cystamine pretreatment will prevent CCl₄-induced hepatic damage by inhibiting the bioactivation of CCl₄. Cystamine-induced hypothermia did not cause a delay in the appearance of maximal hepatic damage. Cystamine also did not stimulate hepatic protein synthesis in intoxicated rats. Although cystamine was reduced to cysteamine in the livers of galactosamine treated rats the hepatic sulfhydryl content was only transiently affected by cystamine. Cystamine did not reduce toxicant-induced hepatic calcium accumulation, despite the fact that the influx of extracellular calcium into toxicant damaged cells is considered by many to be an irreversible event causing cell death. Cystamine also did not alter subcellular calcium distribution in toxicant treated rats or enhance recovery of microsomal calcium sequestration in CCl₄ treated rats. Since cystamine is metabolized to cysteamine in vivo and cysteamine can chelate calcium the effect of chelating agents and cysteamine analogs on galactosamine-induced hepatic damage was tested. Therapeutic effects were observed for the calcium chelators EDTA and EGTA, agents with a chelating structure similar to cysteamine (ie. a free amine and a free sulfhydryl on adjacent carbons), or agents which may be metabolized t0 such structures. The results suggest that calcium chelation may be a mechanism of therapeutic action in chemically-induced hepatotoxicity. A reduction of free calcium concentration via chelation would explain reduced cytotoxic consequences of toxicant-induced hepatic calcium accumulation.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Toxicology, Experimental.; Acetaminophen -- Toxicology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmacology and Toxicology; Graduate College
Degree Grantor:
University of Arizona

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleCYSTAMINE TREATMENT OF CHEMICALLY-INDUCED HEPATOTOXICITY.en_US
dc.creatorMACDONALD, JOHN ROBERT.en_US
dc.contributor.authorMACDONALD, JOHN ROBERT.en_US
dc.date.issued1984en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractThere are few examples of therapeutic treatments in chemically-induced toxicity compared to pretreatments that protect against chemical injury. Cystamine treatment 12 hours after carbon tetrachloride (CCl₄) was reported to have therapeutic effects on CCl₄-induced hepatic necrosis via an unknown mechanism. The objectives of this project were to develop. quantitative animal models to characterize cystamine treatment of chemically-induced hepatotoxicity and to use the models to investigate possible mechanisms of the therapeutic effect. Cystamine produced dose related therapeutic effects against both CCl₄ and galactosamine-induced hepatic necrosis in male Sprague-Dawley rats. The therapeutic effect on galactosamine-induced damage demonstrated that cystamine has therapeutic effects that are unrelated to inhibition of early biochemical events initiating damage. This was an important finding since cystamine pretreatment will prevent CCl₄-induced hepatic damage by inhibiting the bioactivation of CCl₄. Cystamine-induced hypothermia did not cause a delay in the appearance of maximal hepatic damage. Cystamine also did not stimulate hepatic protein synthesis in intoxicated rats. Although cystamine was reduced to cysteamine in the livers of galactosamine treated rats the hepatic sulfhydryl content was only transiently affected by cystamine. Cystamine did not reduce toxicant-induced hepatic calcium accumulation, despite the fact that the influx of extracellular calcium into toxicant damaged cells is considered by many to be an irreversible event causing cell death. Cystamine also did not alter subcellular calcium distribution in toxicant treated rats or enhance recovery of microsomal calcium sequestration in CCl₄ treated rats. Since cystamine is metabolized to cysteamine in vivo and cysteamine can chelate calcium the effect of chelating agents and cysteamine analogs on galactosamine-induced hepatic damage was tested. Therapeutic effects were observed for the calcium chelators EDTA and EGTA, agents with a chelating structure similar to cysteamine (ie. a free amine and a free sulfhydryl on adjacent carbons), or agents which may be metabolized t0 such structures. The results suggest that calcium chelation may be a mechanism of therapeutic action in chemically-induced hepatotoxicity. A reduction of free calcium concentration via chelation would explain reduced cytotoxic consequences of toxicant-induced hepatic calcium accumulation.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectToxicology, Experimental.en_US
dc.subjectAcetaminophen -- Toxicology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmacology and Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.committeememberHuxtable, Ryanen_US
dc.contributor.committeememberLindell, Tomen_US
dc.contributor.committeememberBowden, Timen_US
dc.contributor.committeememberBrendel, Klausen_US
dc.identifier.proquest8501914en_US
dc.identifier.oclc693346680en_US
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