NITROXYL ANALOGS AS INHIBITORS OF ALDEHYDE DEHYDROGENASE - C-NITROSO COMPOUNDS

We previously postulated that the catalase-mediated oxidation of cyana mide leads to the formation of the unstable intermediate, N-hydroxycya namide, which spontaneously decomposes to nitroxyl, the putative inhib itor of aldehyde dehydrogenase (EC 1.2.1.3; AlDH). Since it was not po ssible to provide direct evidence for the inhibition of AlDH by nitrox yl, we examined the activity of three representative substituted nitro xyls (C-nitroso compounds), viz. nitrosobenzene (NB), 1-nitrosoadamant ane (NA), and 2-methyl-2-nitrosopropane (MNP), as direct inhibitors of yeast AlDH in vitro. While NB and NA were highly effective inhibitors in this system exhibiting IC50 values of 2.5 and 8.6 muM, respectivel y, MNP was considerably less effective with an Ic50 of 0.15 mM. When t ested in vivo, NA did not show any inhibitory activity on the hepatic AlDH, possibly due to the lack of site-specific delivery of the active monomeric form of this compound. However, NB at a low dose did inhibi t hepatic AlDH as reflected by an increase in blood acetaldehyde level s. These results attest to the abilities of NB and NA to act as direct inhibitors of AlDH analogous to nitroxyl itself.