The
sulfur-centered compound
dimethylthiourea (
DMTU) affords
antioxidant protection in animal models of
acute lung injury, an effect that has been attributed to its
OH. scavenging properties. Although
DMTU can also react with H2O2 in certain experimental systems, the effect of
DMTU on the neutrophil
myeloperoxidase (MPO) pathway has not been studied.
DMTU (1-10 mM) completely blocked stable
oxidants and
hypochlorous acid formation by
phorbol myristate acetate- and
zymosan-stimulated neutrophils.
DMTU also provided complete inhibition when incubated with cell-free supernatants after the formation of the MPO products.
DMTU prevented the oxidative inactivation of
alpha 1-antitrypsin by neutrophil-stable
oxidants. Evidence that
DMTU was oxidized by the MPO products was obtained by titration of oxidized
DMTU with
reduced glutathione. Surprisingly, supernatants from cells incubated with
DMTU (10 mM) consumed two- to threefold higher amounts of
reduced glutathione than supernatants from cells incubated with
taurine (15 mM). Metabolic studies with stimulated neutrophils and experiments with the MPO
enzyme system in a cell-free system suggested that
DMTU acts by scavenging the products of the MPO pathway rather than by blocking H2O2 production in the intact cell. These findings demonstrate that
DMTU blocks the neutrophil MPO pathway in addition to its known ability to scavenge other reactive O2 species. The capacity of
DMTU to scavenge MPO products may explain some of its protective effects in
acute lung injury.