A stable, low molecular weight mimic of superoxide dismutase (SOD) activity would be exceedingly useful from both experimental and practical points of view. Many complexes of Cu(II) have already been examined and, although active catalysts of the dismutation of O2- in simple chemically-defined systems, they are of little use in biological systems because a variety of proteins, including serum albumin, can strip them of their Cu(II) and thus inactivate them. We have found that desferrioxamine forms a 1:1 complex with Mn(II) which is stable enough to persist in the presence of serum albumin, or in the presence of the mixture of soluble proteins present in lysates of bacterial cells, and which mimics the activity of SOD. We have also noted the presence, in extracts of myocardium, of a low molecular weight, heat stable compound which complexes Cu(II) or Mn(II) yielding a stable and efficient mimic of SOD. We will isolate and identify this substance. We will study the mechanisms of the catalysis of the dismutation of O2- by Mn(II) and Cu(II) complexes of this substance and of desferrioxamine. We will measure the rate constants of the reactions involved in the catalytic cycles. We will examine the abilities of these SOD mimics to cross cell envelopes and to provide protection against the toxicities of hyperoxia and against the oxygen-dependent toxicities of viologens and quinones. We will test whether these SOD mimics decrease the inductions of SOD in Escherichia coli which are caused by oxygenand by paraquat. These studies will then be extended to cultured mammalian cells. We will see whether these compounds can protect algae against the toxicity of paraquat and if encouraging results are obtained will then extend these studies to a simple flowering plant such as duckweed. We would also like to use these compounds to test the free radical theory of aging. Thus, when added to the culture medium, do they extend the lifespan of a free-living nematode such as Caenorhabditis elegans? Given encouraging results with the nematode the same question could be explored with mice.
| Kawabata, T T; Lin, W Q; Ladics, G S (1992) Suppression of the murine gut mucosal IgA response to cholera toxin with oral cyclosporine. Fundam Appl Toxicol 19:575-83 |
| Bhuyan, K C; Bhuyan, D K; Chiu, W et al. (1991) Desferal-Mn(III) in the therapy of diquat-induced cataract in rabbit. Arch Biochem Biophys 288:525-32 |
