Persistent Link:
http://hdl.handle.net/10150/280532
Title:
The role of acetylation in the hepatotoxicity of hydrazine
Author:
Richards, Victoria Elizabeth
Issue Date:
2004
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:
Isoniazid (INH) is an antimicrobial used around the world in the treatment and chemoprophylaxis of tuberculosis. Hepatotoxicity is a well-recognized adverse effect of INH therapy. Metabolites of INH, namely hydrazine (HD) and acetylhydrazine (AcHD), are believed to be responsible for this hepatotoxicity. Studies were initiated to test the hypothesis that HD and not AcHD administration results in alterations in hepatic lipid homeostasis. In adult male C57B1/6J mice doses up to 300 mg AcHD/kg, p.o. did not produce liver damage. In contrast, exposure to HD resulted in time- and dose-dependent decreases in plasma cholesterol as well as lipid accumulation leading to liver damage. Hepatic gene expression profiles were determined after administration of HD or AcHD (100 mg/kg, p.o.). The expression of genes involved in lipid synthesis, transport and metabolism, as well as genes associated with necrosis were altered by HD In contrast, AcHD produced fewer changes and did not result in the differential expression of genes involved in lipid accumulation or necrosis. Several of the genes changed by HD exposure are regulated by PPARalpha. The involvement of PPARalpha in HD-mediated steatosis was investigated in PPARalpha-deficient mice. Administration of HD to these mice induced greater hepatic lipid accumulation and macrovesicular degeneration than did its administration to wild-type mice. This is consistent with the role of PPARalpha in removing lipids from liver. The pathology and the microarray data suggest that the PPARalpha-deficient mice are less capable of meeting the demands of HD-mediated increases in hepatic lipid presentation. In the wild-type animals, PPARalpha is activated in response to HD-induced increases in fatty acids. Consequently, these mice are better able to compensate for the lipid accumulation. This is the first demonstration of a critical role for PPARalpha in response to HD-induced steatosis.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Health Sciences, Toxicology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmacology and Toxicology
Degree Grantor:
University of Arizona
Advisor:
McQueen, Charlene A.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleThe role of acetylation in the hepatotoxicity of hydrazineen_US
dc.creatorRichards, Victoria Elizabethen_US
dc.contributor.authorRichards, Victoria Elizabethen_US
dc.date.issued2004en_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.abstractIsoniazid (INH) is an antimicrobial used around the world in the treatment and chemoprophylaxis of tuberculosis. Hepatotoxicity is a well-recognized adverse effect of INH therapy. Metabolites of INH, namely hydrazine (HD) and acetylhydrazine (AcHD), are believed to be responsible for this hepatotoxicity. Studies were initiated to test the hypothesis that HD and not AcHD administration results in alterations in hepatic lipid homeostasis. In adult male C57B1/6J mice doses up to 300 mg AcHD/kg, p.o. did not produce liver damage. In contrast, exposure to HD resulted in time- and dose-dependent decreases in plasma cholesterol as well as lipid accumulation leading to liver damage. Hepatic gene expression profiles were determined after administration of HD or AcHD (100 mg/kg, p.o.). The expression of genes involved in lipid synthesis, transport and metabolism, as well as genes associated with necrosis were altered by HD In contrast, AcHD produced fewer changes and did not result in the differential expression of genes involved in lipid accumulation or necrosis. Several of the genes changed by HD exposure are regulated by PPARalpha. The involvement of PPARalpha in HD-mediated steatosis was investigated in PPARalpha-deficient mice. Administration of HD to these mice induced greater hepatic lipid accumulation and macrovesicular degeneration than did its administration to wild-type mice. This is consistent with the role of PPARalpha in removing lipids from liver. The pathology and the microarray data suggest that the PPARalpha-deficient mice are less capable of meeting the demands of HD-mediated increases in hepatic lipid presentation. In the wild-type animals, PPARalpha is activated in response to HD-induced increases in fatty acids. Consequently, these mice are better able to compensate for the lipid accumulation. This is the first demonstration of a critical role for PPARalpha in response to HD-induced steatosis.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectHealth Sciences, Toxicology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacology and Toxicologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorMcQueen, Charlene A.en_US
dc.identifier.proquest3131635en_US
dc.identifier.bibrecord.b46709502en_US
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