Oxidation mechanism of hydroxamic acids forming HNO and NO. implications for biological activity

Hydroxamic acids (RC(O)NHOH, HXs) display interesting chemical and biological properties. The pharmacological effects of HXs have been partially attributed to their ability to serve as HNO- or NO-donors under oxidative stress. We have demonstrated that one-electron oxidation of HXs by radiolytically borne radicals yields the respective transient nitroxide radicals, which decompose bimolecularly forming HNO. HXs oxidation by the metmyoglobin and H₂O₂ reactions system involves relatively milder oxidants such as ferryl myoglobin, which oxidize not only HXs but also the nitroxide radical, HNO and NO. The distinction between the effects of NO and HNO in vivo is masked by the reversible redox exchange between these two congeners and due to the Janus-faced behavior of NO and HNO. Acetohydroxamic acid potentiates H₂O₂-induced killing of Escherichia coli, whereas suberoylanilide hydroxamic acid (SAHA) protects mammalian cells subjected to oxidative stress. These results are similar to those observed for NO implying that in these systems HXs serve as NO-donors. In contrast, the effect of acetohydroxamic acid on Bacillus subtilis subjected to oxidative stress is similar to that of HNO. SAHA, but not valproic acid lacking the hydroxamate moiety, enhances the radiosensitization of hypoxic tumor cells in vitro. Given that NO, but not HNO, is a hypoxic cell radiosensitizer, the enhancement of tumor radioresponse by SAHA might involve its ability to serve as a NO-donor. It is concluded that HXs form HNO under oxidative stress, but can be considered as NO-donors if HNO oxidation competes with N₂O formation and with its reaction with potential biological targets.