Theor Biol Med Model. 2008 Apr 28;5(1):8 [Epub ahead of print]

A mathematical model of glutathione metabolism.

Reed MC, Thomas RL, Pavisic J, James SJ, Ulrich CM, Nijhout HF.

BACKGROUND: Glutathione (GSH) plays an important role in anti-oxidant defense and detoxification reactions. It is primarily synthesized in the liver by the transulfuration 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 Alzheimeras disease, Parkinsonas 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 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.

CONCLUSIONS: 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 trisomy 21, an increase in oxidative stress, and subsequent increased transport of GSH precursors by peripheral cells can explain the metabolic profile of Down syndrome. The model also correctly simulates the metabolic profile of autism when oxidative stress is substantially increased, the adenosine concentration is raised, and the uptake of GSH precursors by peripheral tissues is increased. Finally, we discuss how individual variation arises and its consequences for one-carbon and glutathione metabolism.

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