Title

Investigation of biochemical mechanisms responsible for peroxisome proliferator-mediated protection from acetaminophen

Date of Completion

January 2006

Keywords

Health Sciences, Toxicology

Degree

Ph.D.

Abstract

Peroxisome proliferators are structurally diverse compounds that include industrial chemicals, environmental pollutants, and therapeutic agents. The responses to these chemicals are most profound in rodent livers, increasing both the size and number of peroxisomes. Exposure to peroxisome proliferators modulates numerous biochemical pathways, influencing transcriptional regulation, lipid metabolism, immune function, and hepatocellular proliferation. Another effect of peroxisome proliferators is that they protect the liver against the toxic actions of chemicals like acetaminophen (APAP). ^ The first set of studies investigates the potential hepatoprotective role of NAD(P)H:Quinone Oxidoreductase 1 (NQO1). Mechanistically, NQO1 could detoxify APAP directly through quinone reduction of NAPQI or indirectly by neutralizing superoxide and/or enhancing endogenous antioxidants. The second mechanistic studies investigate the regulation, expression, and localization of hepatic transporters in response to CFB treatment. Previous studies have shown that modulation of hepatic transporters by endogenous ligands and xenobiotics may represent a coordinated, hepatoprotective response of the liver against cellular distress. Altered disposition of xenobiotics, metabolites, and mediators of toxicity may contribute to peroxisome proliferator-mediated hepatoprotection. ^ The final studies examined the role of vanin-1 in CFB-mediated hepatoprotection. Differential gene expression profiling analysis was utilized to identify potential mechanistic pathways of PPARα-mediated hepatoprotection. Our analysis identified vanin-1, an enzyme that produces cysteamine and cystamine, potent antioxidants. Both cysteamine and cystamine are capable of preventing APAP hepatotoxicity in rodents and humans. Administration of peroxisome proliferators has been shown to increase the mRNA levels of vanin-1, which may increase hepatic cysteamine and cystamine, providing hepatoprotection. ^ This investigation provides evidence suggesting that CFB-mediated hepatoprotection results from multiple mechanisms, including enhanced detoxification and anti-oxidant pathways as well as altered disposition of xenobiotics and mediators of toxicity. (Abstract shortened by UMI.) ^