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Vol. 285, Issue 2, 608-618, May 1998
Department of Pharmacology, Wayne State University School of
Medicine, Detroit, Michigan
The role of organic anion transporters in the mitochondrial uptake of
glutathione (GSH) was investigated by assessing competition with
substrates or inhibition with inhibitors of specific carriers and
modulation of mitochondrial energetics. Potential artifacts in the
transport methodology, including contamination of matrix space with
extramitochondrial fluid, changes in matrix volume during incubations,
efflux of transported GSH during sample processing, induction of the
membrane permeability transition, contamination of the mitochondrial
preparation with plasma membranes and GSH degradation, were corrected
or eliminated. Substrates (i.e., malate, succinate) and
an inhibitor (i.e., butylmalonate) of the dicarboxylate carrier, an inhibitor (i.e., phenylsuccinate) of the
2-oxoglutarate carrier, and glutamate produced significant inhibition
of GSH uptake whereas substrates and inhibitors of the mono- and
tricarboxylate carriers were generally without effect.
Phosphoenolpyruvate, which is a substrate for the tricarboxylate
carrier, inhibited GSH uptake, but this was due to induction of the
membrane permeability transition and not to competition for uptake.
Although glutamate inhibited GSH uptake, the converse did not occur.
GSH uptake was pH-independent and aspartate had no effect, which
suggest that the glutamate and glutamate-aspartate carriers are not
involved in GSH uptake but that the glutamyl residue of GSH may be
important in its transport. GSH uptake was dependent on phosphate and
ATP generation. Hence, we conclude that both the dicarboxylate and
2-oxoglutarate carriers of the inner membrane can catalyze uptake of
GSH into the matrix. The function of an additional, novel transporter
cannot be excluded at present. This is the first study to define the
function of mitochondrial anion carriers in GSH transport.
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