CARBETHOXYLATING AGENTS AS INHIBITORS OF ALDEHYDE DEHYDROGENASE

N, O-Dicarbethoxy-4-chlorobenzenesulfohydroxamate (1c) and O-carbethox y-N-hydroxysaccharin (6), both potential carbethoxylating agents, inhi bited yeast aldehyde dehydrogenase (AlDH) with IC50)s Of 24 and 56 mu M, respectively. The esterase activity of the enzyme was commensurably inhibited. AlDH activity was only partially restored on incubation wi th mercaptoethanol (20 mM) for 1 h. On incubation with rat plasma, 1c liberated nitroxyl, a potent inhibitor of AlDH. Under the same conditi ons, nitroxyl generation from 6 was minimal, a result compatible with a previous observation that nitroxyl generation from N-hydrxxysacchari n (7), the product of the hydrolysis of the carbethoxy group of 6, was minimal at physiological pH. Since chemical carbethoxylating agents r epresented by the O-carbethoxylated N-hydroxyphthalimide, 1-hydroxyben zotriazole, and N-hydroxysuccinimide (8, 9, and 10, respectively) like wise inhibited yeast AlDH, albeit with IC50's 1 Order of magnitude hig her, we postulate that 1c and 6 act as irreversible inhibitors of AlDH by carbethoxylating the active site of the enzyme.