NITROXIDE METABOLISM IN ADENOVIRUS TRANSFORMED CELLS

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Krishna et al (Proc. Natl. Acad. Sci. USA 89:5537-5541, 1992) showed that nitroxides act as superoxide disumate (SOD) mimetics but are oxidized to the oxoammonium instead of reduced to the hydroxylamine (as they previously stated, Samuni et al (J. Biol. Chem. 263:17921-17924, 1988). Our data supports their more recent conclusions. In our mechanism, TEMPOL is reduced by two mechanisms, 1) by one electron reduction via the electron transport system and 2) by two electron reduction from the oxoammonium ion produced by SOD-like activity of the nitroxide. Peroxide re-oxidizes the hydroxylamine to the nitroxide and plays a major role in determining overall nitroxide reduction rates. Catalase activity in the 983.2 cells is only 5% of that in the BHK cells which may allow excess peroxide to recycle the hydroxylamine back to the nitroxide. This would explain the lower overall TEMPOL reduction rates seen in 983.2 cells compared to BHK cells. Our model and the evidence in support of it was presen ted in detail during 1995, and some further progress was made in 1996 and 1997. Supported by NIH grants R15 GM 44365-01 to PDM and R15 CA52091-01A1 to LAL.