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Vol. 53, Issue 4, 638-648, April 1998
Department of Biochemistry, Mount Sinai School of Medicine, New
York, New York 10029
Two Hep G2 subclones overexpressing CYP2E1 were established with the
use of transfection and limited dilution screening techniques. The Hep
G2-CI2E1-43 and -47 (E47) cells (transduced Hep G2 subclones that
overexpress CYP2E1) grew at a slower rate than parental Hep G2 cells or
control subclones that do not express CYP2E1, but remained fully
viable. When GSH synthesis was inhibited by treatment with buthionine
sulfoximine, GSH levels rapidly declined in E47 cells but not control
cells, which is most likely a reflection of CYP2E1-catalyzed formation
of reactive oxygen species. Under these conditions of GSH depletion,
cytotoxicity and apoptosis were found only with the E47 cells. Low
levels of lipid peroxidation were found in the E47 cells, which became
more pronounced after GSH depletion. The antioxidants vitamin E,
vitamin C, or trolox prevented the lipid peroxidation as well as the
cytotoxicity and apoptosis, as did transfection with plasmid containing
antisense CYP2E1 or overexpression of Bcl-2. Levels of ATP were lower
in E47 cells because of damage to mitochondrial complex I. When GSH was
depleted, oxygen uptake was markedly decreased with all substrates in
the E47 extracts. Vitamin E completely prevented the decrease in oxygen
uptake. Under conditions of CYP2E1 overexpression, two modes of
CYP2E1-dependent toxicity can be observed in Hep G2 cells: a slower
growth rate when cellular GSH levels are maintained and a loss of
cellular viability when cellular GSH levels are depleted. Elevated
lipid peroxidation plays an important role in the CYP2E1-dependent toxicity and apoptosis. This direct toxicity of overexpressed CYP2E1
may reflect the ability of this enzyme to generate reactive oxygen
species even in the absence of added metabolic substrate.
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