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A mathematical model of glutathione metabolism
Reed M., Thomas R., Pavisic J.,
James J.
Theoretical Biology and Medical Modelling 2008, 5:8
doi:10.1186/1742-4682-5-8
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Background: Glutathione (GSH)
plays an important role in anti-oxidant defense and detoxification
reactions. It is primarily synthesized in the liver by the
transsulfuration pathway and exported to provide precursors for in situ
GSH synthesis by other tissues. Deficits in glutathione have been
implicated in aging and a host of diseases including Alzheimer's
disease, Parkinson's disease, cardiovascular disease, cancer, Down
syndrome and autism.
Approach: We explore the properties of glutathione metabolism in the
liver by experimenting with a mathematical model of one-carbon
metabolism, the transsulfuration pathway, and glutathione synthesis,
transport, and breakdown. The model is based on known properties of the
enzymes and the regulation of those enzymes by oxidative stress. We
explore the half-life of glutathione, the regulation of glutathione
synthesis, and its sensitivity to fluctuations in amino acid input. We
use the model to simulate the metabolic profiles previously observed in
Down syndrome
and autism and compare the model results to clinical data.
Conclusion: We show that the glutathione pools in hepatic cells and in
the blood are quite insensitive to fluctuations in amino acid input and
offer an explanation based on model predictions. In contrast, we show
that hepatic glutathione pools are highly sensitive to the level of
oxidative stress. The model shows that over-expression of genes on
chromosome 21 and an increase in oxidative stress can explain the
metabolic profile of Down syndrome. The model also correctly simulates
the metabolic profile of autism when oxidative stress is substantially
increased and the adenosine concentration is raised. Finally, we discuss
how individual variation arises and its consequences for one-carbon and
glutathione metabolism.
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