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ToxSci Advance Access originally published online on July 28, 2004
Toxicological Sciences 2004 82(1):318-332; doi:10.1093/toxsci/kfh232
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Toxicological Sciences vol. 82 no. 1 © Society of Toxicology 2004; all rights reserved.

Hepatic Gene Expression and Lipid Homeostasis in C57Bl/6 Mice Exposed to Hydrazine or Acetylhydrazine

Victoria E. Richards*, Binh Chau*, M. Randy White{dagger} and Charlene A. McQueen*,1

* Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721; and {dagger} PRI, Mt. Vernon Pathology, Evansville, Indiana 47721

Received May 12, 2004; accepted July 23, 2004

Hydrazine (HD) and acetylhydrazine (AcHD) are metabolites of the antituberculosis drug isoniazid (INH) that have been implicated in INH-induced liver damage. The hepatotoxicity of AcHD and HD were compared in adult male C57Bl/6J mice by evaluating hepatic histopathology, plasma biochemistry, and hepatic gene expression. By all measures, HD had significantly greater effects than AcHD. There was no evidence of liver damage following exposure to AcHD (300 mg/kg, po). However, HD at this dose caused marked hepatic necrosis, macrovesicular degeneration, and steatosis. Lipid accumulation was initiated 2 h after HD exposure, with hepatic macrovesicular degeneration evident after 4 h, and severe necrosis by 36 h. Gene expression profiles were compared 24 h following 100 mg/kg po of HD or AcHD. HD changed the hepatic expression of more genes than AcHD, particularly lipid synthesis, transport, and metabolism genes that may be involved in steatosis. Hepatic expression of genes regulated by peroxisome proliferator activated receptors (PPAR) and sterol regulatory element binding protein (SREBP) transcription factors was increased only by HD. The hepatotoxicty and hepatic gene expression profile of HD, but not AcHD, indicate that exposure to HD initiates a process whereby the production and intracellular transport of hepatic lipids is favored over the removal of fatty acids and their metabolites.

Key Words: hydrazine; acetylhydrazine; cDNA microarray; steatosis; hepatotoxicity; peroxisome proliferator-activated receptor.


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