Inhibitor Of Aldehyde Oxidase Research Articles

Cyclophosphamide potentiation and aldehyde oxidase inhibition by phosphorylated aldehydes and acetals.

Fourteen phosphorylated acetals and aldehydes were synthesized for testing in vitro as inhibitors or substrates of aldehyde oxidase, an enzyme involved in the conversion of aldophosphamide to inactive carboxyphosphamide, and for concurrent in vivo administration with cyclophosphamide to mice bearing L1210 ascites tumor cells. Five phosphorus derivatives gave Ki values of 0.1--0.3 mM compared to 0.03 mM for pyridoxal, as determined in aldehyde oxidase assays using N-methylnicotinamide as the substrate. The most active phosphorus inhibitor, ethyl phenyl(2-formylethyl)phosphinate (2b), and pyridoxal were further shown to give competitive and mixed inhibition, respectively. Three aldehydes, administered concurrently with cyclophosphamide, produced greater increases in life span of L1210-implanted mice than did pyridoxal. All four agents gave an average increase in life span greater than 50% over that shown by cyclophosphamide alone.

Human liver aldehyde oxidase: differential inhibition of oxidation of charged and uncharged substrates.

HUMAN LIVER ALDEHYDE OXIDASE (ALDEHYDE: O(2) oxidoreductase, EC 1.2.3.1) has been purified 60-fold and some of its properties studied. Like aldehyde oxidase from other mammalian species, human liver aldehyde oxidase is an enzyme with dual substrate specificity, possessing the ability to catalyze not only the oxidation of aldehydes to the corresponding carboxylic acids, but also the hydroxylation of a number of nonaldehydic heterocyclic compounds; its relative activity towards the latter group of substrates is low, however, when compared with that of liver aldehyde oxidase from rabbit and guinea pig. When the aromatic aldehyde benzaldehyde is used as substrate, human liver aldehyde oxidase, like the rabbit enzyme, is strongly inhibited by menadione, estradiol-17beta, antimycin A, Triton X-100, and N-alkylphenothiazines; the human enzyme differs from the rabbit enzyme, however, in being relatively insensitive to oligomycin and Amytal. Like the rabbit enzyme, the human enzyme can catalyze the 3-hydroxylation of phenazine methosulfate (PMS) and the 6-hydroxylation of N-methylnicotinamide (NMN). With the rabbit enzyme, however, the aerobic hydroxylation of these substrates proceeds by a conventional mechanism, while with the human enzyme, the aerobic hydroxylation of PMS and NMN is anomalous in that the reaction is inhibited only by agents with affinity for the substrate-binding site, such as cyanide and N-alkylphenothiazines, and not by agents which inhibit the "internal electron transport chain" of the enzyme, such as menadione and diethylstilbestrol. This mode of oxidation appears to be unique to substrates with a positively charged quaternary nitrogen; the hydroxylation of other nonaldehydic heterocyclic substrates for the human enzyme is sensitive to conventional aldehyde oxidase inhibitors.

Metabolism of vanillin and related substances in the rat.

Intraperitoneal administration of vanillin (4-hydroxy-3-methoxybenzaldehyde) to rats gave rise to a number of urinary products, chief among which was vanillic acid, in both free and conjugated forms. Other metabolites were conjugated vanillin, conjugated vanillyl alcohol, and catechol (pyrocatechol). Catechol continued to be formed even after treatment of the animals with neomycin and streptomycin for 72 hours before the vanillin was administered. Besides vanillin, the following exogenous compounds were shown to be sources of urinary catechol: protocatechuic aldehyde, protocatechuic acid, vanillic acid, and guaiacol. Noradrenalone, adrenalone, and isoprenalone were not precursors. Treatment of rats with disulfiram, an inhibitor of aldehyde oxidase, before the administration of vanillin resulted in a decrease in the proportion of vanillic acid formed and an increase in that of vanillyl alcohol. Disulfiram also interfered with the formation of catechol from guaiacol.

Inhibition of Aldehyde Oxidase from Liver by Tetraethylthiuramdisulphide (Antabuse).

Inhibition of Aldehyde Oxidase from Liver by Tetraethylthiuramdisulphide (Antabuse).