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Vol. 54, Issue 6, 1024-1035, December 1998
Department of Biochemistry, Mount Sinai School of Medicine, New
York, New York 10029
Iron can potentiate the toxicity of ethanol. Ethanol increases the
content of cytochrome P450 2E1 (CYP2E1), which generates reactive
oxygen species, and transition metals such as iron are powerful
catalysts of hydroxyl radical formation and lipid peroxidation. Experiments were carried out to attempt to link CYP2E1, iron, and
oxidative stress as a potential mechanism by which iron increases ethanol toxicity. The addition of ferric-nitrilotriacetate (Fe-NTA) to
a HepG2 cell line expressing CYP2E1 decreased cell viability, whereas
little effect was observed in control cells not expressing CYP2E1.
Toxicity in the CYP2E1-expressing cells was markedly enhanced after the
depletion of glutathione. Lipid peroxidation was increased by Fe-NTA,
especially in cell extracts and medium from the CYP2E1-expressing cells. Toxicity was completely prevented by vitamin E or by
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, which also
decreased the lipid peroxidation. Levels of ATP were lowered by Fe-NTA,
and this was associated with a decreased rate of oxygen consumption by
permeabilized cells with substrates donating electrons to complexes I,
II, and IV of the respiratory chain. This mitochondrial damage was
prevented by vitamin E. Toxicity was accompanied by DNA fragmentation,
and this fragmentation was prevented by antioxidants. Overexpression of
bcl-2 decreased the toxicity and DNA fragmentation produced by the
combination of CYP2E1 plus Fe-NTA, as did a peptide inhibitor of
caspase 3. These results suggest that elevated generation of reactive
oxygen species in HepG2 cells expressing CYP2E1 leads to lipid
peroxidation in the presence of iron, and the ensuing prooxidative
state damages mitochondria, releasing factors that activate caspase 3, leading to a loss in cell viability and DNA fragmentation.
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