Hemochromatosis refers to a state of iron overload. Numerous cellular changes from altered gene expression to oxidative cellular damage and cytotoxicity have been observed in iron-loaded livers of hemochromatosis patients. Eventually, chronic iron overload leads to fibrosis. The liver becomes cirrhotic and hepatocarcinomas may arise. Dr. Isom's goal is to addres the isolated issue of how iron overload alters the function of well-differentiated hepatocytes in the absence of other cell types. The hypothesis being tested is: Iron loading of hepatocytes in long-term DMSO culture induces specific types of cellular damage that are potentated if the cells are treated with cytokines. Iron overloaded hepatocytes in long term DMS culture will be used: 1) to determine what types of cellular damage occur in acute and chronic iron overloaded hepatocytes; 2) to determine whether the method by which iron is taken up by hepatocytes or the antioxidant environment of the hepatocyte in the process of iron overload affects the reversibility of the iron overload process and/or the type and extent of cellular damage; and 3 to determine the effect of TNF alpha treatment on cellular injury, expression of ferritin and other gene products associated with iron homeostasis in iron overloaded hepatocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054482-04
Application #
6381244
Study Section
Special Emphasis Panel (ZRG2-MEP (03))
Program Officer
Doo, Edward
Project Start
1998-09-01
Project End
2002-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
4
Fiscal Year
2001
Total Cost
$230,186
Indirect Cost
Name
Pennsylvania State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Moon, Mi Sun; McDevitt, Emily I; Zhu, Junjia et al. (2012) Elevated hepatic iron activates NF-E2-related factor 2-regulated pathway in a dietary iron overload mouse model. Toxicol Sci 129:74-85
Moon, Mi Sun; Richie, John P; Isom, Harriet C (2010) Iron potentiates acetaminophen-induced oxidative stress and mitochondrial dysfunction in cultured mouse hepatocytes. Toxicol Sci 118:119-27
Bilello, John P; Cable, Edward E; Isom, Harriet C (2003) Expression of E-cadherin and other paracellular junction genes is decreased in iron-loaded hepatocytes. Am J Pathol 162:1323-38
Bilello, J P; Cable, E E; Myers, R L et al. (2003) Role of paracellular junction complexes in baculovirus-mediated gene transfer to nondividing rat hepatocytes. Gene Ther 10:733-49
Malecki, Elise A; Cable, Edward E; Isom, Harriet C et al. (2002) The lipophilic iron compound TMH-ferrocene [(3,5,5-trimethylhexanoyl)ferrocene] increases iron concentrations, neuronal L-ferritin, and heme oxygenase in brains of BALB/c mice. Biol Trace Elem Res 86:73-84
Cable, Edward E; Kuhn, Benjamin R; Isom, Harriet C (2002) Effects of modulators of protein phosphorylation on heme metabolism in human hepatic cells: induction of delta-aminolevulinic synthase mRNA and protein by okadaic acid. DNA Cell Biol 21:323-32
Bilello, J P; Delaney 4th, W E; Boyce, F M et al. (2001) Transient disruption of intercellular junctions enables baculovirus entry into nondividing hepatocytes. J Virol 75:9857-71
Cable, E E; Miller, T G; Isom, H C (2000) Regulation of heme metabolism in rat hepatocytes and hepatocyte cell lines: delta-aminolevulinic acid synthase and heme oxygenase are regulated by different heme-dependent mechanisms. Arch Biochem Biophys 384:280-95
Cable, E E; Isom, H C (1999) Metabolism of 3,5,5-trimethylhexanoyl-ferrocene by rat liver: release of iron from 3,5,5-trimethylhexanoyl-ferrocene by a microsomal, phenobarbital-inducible cytochrome P-450. Drug Metab Dispos 27:255-60