One of the most important antioxidant enzymes is superoxide dismutase (SOD), which catalyses the dismutation of superoxide radicals to hydrogen peroxide. The gene for CuZnSOD lies in humans on chromosome 21 and its activity is increased in patients with Down syndrome. But instead of being beneficial, increased lipid peroxidation is associated with this increased expression and also studies on bacteria and transgenic animals show that high levels of SOD actually lead to increased lipid peroxidation and hypersensitivity to oxidative stress.
Using mathematical models we investigate the question how overexpression of SOD can lead to increased oxidative stress, although it is an antioxidant enzyme. We consider the following possibilities that have been proposed in the literature:
(i) Reaction of H2O2 with CuZnSOD leading to hydroxyl radical formation.
(ii) Superoxide radicals might actually reduce membrane damage by acting as radical chain breaker.
(iii) While detoxifying superoxide radicals SOD cycles between a reduced and oxidised state. At low superoxide levels the intermediates might interact with other redox partners and increase the superoxide reductase (SOR) activity of SOD. This short-circuiting of the SOD cycle could lead to an increased hydrogen peroxide production.
We find that two of the proposed mechanisms are under certain circumstances able to explain the increased oxidative stress caused by SOD. But furthermore we identify an additional mechanism that is of more general nature and agrees well with experimental observations.