Journal of Applied Physiology, Vol 67, Issue 3 1056-1062, Copyright © 1989 by American Physiological Society
Effect of dimethylthiourea on the neutrophil myeloperoxidase pathway
A. L. Sagone Jr, R. M. Husney, M. D. Wewers, D. J. Herzyk and W. B. Davis
Department of Internal Medicine, Ohio State University, Columbus 43210.
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.
