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Glutathione Articles - Cystic Fibrosis
A new model of cystic fibrosis pathology: Lack of transport
of glutathione and its thiocyanate conjugates
Melanie Childers, George Eckel, Alan Himmel, Jim Caldwell
Medical Hypotheses 2006, Vol 68, Issue 1:101-112
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ABSTRACT
Many of the symptoms of cystic fibrosis are not explained by the current
disease mechanisms. Therefore, the authors conducted an extensive
literature review and present a new model of cystic fibrosis pathology,
which is the culmination of this research. Understanding that the cystic
fibrosis transmembrane conductance regulator (CFTR) is responsible for
glutathione (GSH) transport, the authors hypothesize that mutations of
the CFTR, which create abnormal GSH transport, will lead to aberrations
of GSH levels in both the intracellular as well as the extracellular
milieu. These alterations in normal cellular GSH levels affect the redox
state of the cell, thereby affecting the intracellular stress protein,
metallothionein. The authors describe how this disruption of the redox
state caused by excess cellular GSH, will naturally prevent the delivery
of zinc as a cofactor for various enzymatic processes, and how these
disruptions in normal redox may cause alterations in both humoral and
cell-mediated immunity. Moreover, the symptom of thick sticky mucus in
these patients might be explained through the understanding that
oversulfation of mucus is a direct result of elevated cellular GSH and
cysteine. The issues of hyperinflammation, altered pH and the imbalance
of fatty acids that are typical in cystic fibrosis are addressed—all of
which may also be linked to disruptions in GSH homeostasis.
Additionally, this new model of cystic fibrosis pathology, clarifies the
relationship between the CFTR and the multi-drug resistance proteins,
and the lack of cell-mediated immunity by predicting that the substrate
of these proteins is a glutathione adduct of thiocyanate. Finally, a new
therapeutic strategy by using isothiocyanates to rectify the GSH
imbalance and restore the immune system is suggested for the treatment
of cystic fibrosis patients.
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