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.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/280532 |
| Date | January 2004 |
| Creators | Richards, Victoria Elizabeth |
| Contributors | McQueen, Charlene A. |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Dissertation-Reproduction (electronic) |
| 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. |
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