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*
Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520; and
Department of Pediatrics, University of Colorado School of Medicine and National Jewish Medical and Research Center, Denver, CO 80206
During the phagocytic respiratory burst, oxygen is converted to
potent cytotoxic oxidants. Monocytes and macrophages are potentially
long-lived, and we have hypothesized that protective mechanisms against
oxidant stress are varied and fully expressed in these cells. We report
here that the respiratory burst in monocytes is accompanied by an
increase in the uptake of [35S]glutathione
([35S]GSH) after 20–30 min to levels up to 10-fold
greater than those at baseline. By 30 min, 49% of the cell-associated
radioactivity was in the cytosol, 41% was in membrane, and 10% was
associated with the nuclear fraction. GSH uptake was inhibited by
catalase, which removes hydrogen peroxide
(H2O2), and micromolar
H2O2 stimulated GSH uptake effectively in
monocytes and also lymphocytes. Oxidation of GSH to glutathione
disulfide with H2O2 and glutathione peroxidase
prevented uptake. Acivicin, which inhibits GSH breakdown by
-glutamyl transpeptidase (GGT), had no effect on the enhanced uptake
seen during the respiratory burst. Uptake of cysteine or cystine,
possible products of GGT activity, stayed the same or decreased during
the respiratory burst. These results suggest that a GGT-independent
mechanism is responsible for the enhanced GSH uptake seen during the
respiratory burst. We describe here a sodium-independent,
methionine-inhibitable transport system with a
Km (8.5 µM) for GSH approximating the
plasma GSH concentration. These results suggest that monocytes have a
specific GSH transporter that is triggered by the release of
H2O2 during the respiratory burst and that
induces the uptake of GSH into the cell. Such a mechanism has the
potential to protect the phagocyte against oxidant
damage.
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