Blood, 15 August 2002, Vol. 100, No. 4, pp. 1515-1516
CORRESPONDENCE
To the editor:
Oxidation of glutathione peroxidase-deficient red cells by
organic peroxides
Red cells from mice with a disrupted glutathione peroxidase-1
(GSHPx-1) gene have no GSHPx activity, since GSHPx-1 is the only isoform of GSHPx found in the erythrocyte. In a recent article in
Blood,1 we reported that these enzyme-deficient
red cells are not oxidized by exogenous hydrogen peroxide any faster
than wild-type cells. This strongly supports the view that catalase is
the preeminent enzyme protecting red cells from attack by exogenous hydrogen peroxide. However, this conclusion also raises a question about the role of GSHPx in the red cell. In this regard, we noted that
while catalase is completely specific for H2O2,
GSHPx is able to reduce organic peroxides as well, suggesting that the distinctive role of GSHPx might be to detoxify organic peroxides. To
test this, wild-type and GSHPx-deficient red cells2 were exposed to a range of compounds known to hemolyze red cells (cumene peroxide, methylene blue, chloramphenicol, naphthalene,
phenylhydrazine, t-butyl peroxide, primaquine, paraquat). Oxidation of
hemoglobin (Hb) was used as an endpoint for oxidative damage.
Preliminary studies also assayed K efflux, which is increased by
organic peroxides.3,4 However, the alteration in K efflux
was found to follow temporally the oxidation of Hb, indicating that Hb
oxidation was an earlier indicator of oxidative damage. Of these
compounds, the GSHPx-deficient red cells showed differential
sensitivity only to organic peroxides. Figure
1 shows a distinct and reproducible
difference between wild-type and GSHPx-deficient cells in their
sensitivity to organic peroxides.
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| Figure 1.
Oxidation of hemoglobin in intact erythrocytes by
organic peroxides.
 indicate wild-type red cells;  , GSHPx-deficient red
cells.
|
|
What might be the evolutionary benefits of an erythrocyte mechanism for
detoxifying organic peroxides? Are there circumstances when organic
peroxides might arise in animal issues? Circumstantial evidence is
found in the observation that all microorganisms have enzymatic
activities, AhpC/F, that reduce organic peroxides.5-10 Although these enzymes are peroxiredoxins and have no structural relationship to eucaryotic GSHPx, they exhibit similar catalytic capacities and are able to reduce cumene peroxide and t-butyl peroxide.
These enzymes protect the bacterium against damage by organic
peroxides, strengthening their functional similarity to GSHPx.
Interestingly, deletion of genes for these organic peroxide reductases
sometimes,9,10 but not always,8 attenuates
the virulence of pathogenic strains, suggesting that organic peroxides may be part of the macrophage bactericidal response. Reactions between
the H2O2 of the respiratory burst and
unsaturated compounds in the cellular environment would be expected to
generate toxic organic peroxides, providing a rationale for the reduced
virulence phenotype of strains deficient in organic peroxidase
reductase. It would be important for the host organism that its cells
are also able to detoxify such organic peroxides. Thus, we suggest that
protection against organic peroxides produced during phagocyte killing
is a physiological role for GSHPx in red cells.
Robert M. Johnson, Gerard Goyette, Jr, Yaddanapudi Ravindranath, and Ye-Shih Ho
Correspondence: Robert M. Johnson, Department of Biochemistry
and Molecular Biology, Wayne State Medical School, 540 E Canfield,
Detroit, MI 48201; e-mail: rmjohns{at}med.wayne.edu.
Acknowledgments
This work was supported by National Institutes of Health grant
HL56421 (Y-S.H.) and the Ginopolis Fund of Children's Hospital of Michigan.
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