Acetaminophen (APAP) toxicity is a major cause of acute liver failure in the United States today. Mitochondrial permeability transition (MPT) and oxidative stress are important mechanisms in APAP toxicity. Hypoxia inducible factor-1α (HIF-1α) is a transcription factor that regulates cellular homeostasis during hypoxia and is also regulated in response to oxidative stress. The MPT inhibitors cyclosporine (CYC) and trifluoperazine (TFP) have been shown to alter MPT in cellular models of APAP toxicity but have not been well studied in APAP toxicity in the mouse. High dose CYC (50 mg/kg) reduced toxicity and HIF-1α induction but inhibited the metabolism of APAP, a critical mechanism of toxicity. Low dose CYC (10mg/kg) had no effect on metabolism and reduced HIF-1α but did not prevent toxicity. Subsequently, we examined the effect of TFP on HIF-1α induction and toxicity in APAP treated mice. TFP (10 mg/kg) reduced toxicity (ALT and necrosis) and HIF-1α induction without altering metabolism (glutathione depletion, APAP protein adduct formation). Vascular endothelial growth factor (VEGF), a known target of HIF-1α induction was elevated, while proliferating cell nuclear antigen (PCNA), a common marker of hepatocyte regeneration was reduced in the TFP treated mice. TFP mice also had lowered phospholipase activity and prostaglandin E2 (PGE2) levels. Thus, TFP reduced HIF-1α induction and toxicity. TFP also reduced hepatocyte regeneration, likely as a result of lower phospholipase activity and lower PGE2, a known pathway of hepatocyte regeneration in APAP toxicity.
In final studies, the role of neuronal nitric oxide synthase (nNOS) in HIF-1α induction and toxicity was examined. Biochemical indicators (alanine aminotransferase release) differed transiently in the two groups of mice but no difference in necrosis was observed. However, the nNOS KO mice had early evidence of severe hemorrhage and HIF-1α was markedly reduced in nNOS KO mice. Chemokine levels and neutrophil infiltration were greater in the KO mice and followed the onset of hemorrhage. PCNA expression was comparable in the two groups of mice at 24 h. Cumulatively the data indicate an important role for nNOS in HIF-1α induction and the control of vascular homeostasis in APAP toxicity.
|Advisor:||James, Laura P.|
|Commitee:||Gilbert, Kathleen, Hinson, Jack A., Macmillan-crow, Lee Ann, Mayeux, Philip|
|School:||University of Arkansas for Medical Sciences|
|Department:||Interdisciplinary Biomedical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 73/10(E), Dissertation Abstracts International|
|Subjects:||Toxicology, Surgery, Pharmacology, Health care management|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be