A Comparative Study on the Effects of Disulfiram, Cyanamide and 1‐Aminocyclopropanol on the Acetaldehyde Metabolism in Rats

Abstract

1‐aminocyclopropanol (ACP) is a potent inhibitor of aldehyde dehydrogenase (ALDH) in vivo and in vitro. Like cyanamide it has a rapid onset of action in vivo with the highest inhibition occurring after 2‐24 hrs. and a long duration of action like disulfiram with measurable inhibition after 144 hrs. All the three inhibitors decreased the activity of the mitochondrial low‐Km ALDH strongly in vivo, however, in markedly different doses. Cyanamide inhibited the high‐Km ALDH only in vivo, whereas in vitro, the high‐Km ALDH was unaffected by cyanamide but significantly inhibited by disulfiram and ACP. The inhibition produced by the inhibitors appeared to be irreversible. Acetaldehyde protected the low‐Km enzyme at different extents depending on the inhibitor used. The inhibition of ALDH in intoxicated and control rats and its relation to acetaldehyde oxidation and the disulfiram‐ethanol reaction are discussed.

Tryptophan in Alcoholism Treatment I: Kynurenine Metabolites Inhibit the Rat Liver Mitochondrial Low Km Aldehyde Dehydrogenase Activity, Elevate Blood Acetaldehyde Concentration and Induce Aversion to Alcohol

“…However, with KA and 3-HAA, inhibition either remained at its maximal value or gained in strength, suggesting a longer duration and a possible irreversible nature. With disulfiram, its irreversible inhibition ( Marchner and Tottmar, 1978 ) is characterized by a prolonged duration (7–10 days) after a single dose (see, Brien and Loomis, 1985 ). Kinetic studies are clearly required to establish the mechanism(s) of the ALDH inhibition by these kynurenine metabolites.…”

Aldehydes

“…AcH competitively inhibits the oxidation of FA in rat liver mitochondria, suggesting that both of these aldehydes are metabolized by the same enzyme. Substantial quantities of the AcH (at 0.1-2.3 mmol l À1 ) can be oxidized extramitochondrially in rat liver preparations, particularly by microsomal enzymes (Marchner and Tottmar, 1978). Substantial quantities of the AcH (at 0.1-2.3 mmol l À1 ) can be oxidized extramitochondrially in rat liver preparations, particularly by microsomal enzymes (Marchner and Tottmar, 1978).…”

Biochemical Mechanisms of Sirtuin-Directed Protein Acylation in Hepatic Pathologies of Mitochondrial Dysfunction

“…When the capacity for ALDH2 to metabolize acetaldehyde is saturated, this electrophilic metabolite accumulates and generates protein and DNA adducts, contributing to hepatocyte damage and liver dysfunction [146]. Alcohol metabolism contributes directly to mitochondrial protein hyperacetylation whereas sirtuin deacetylase activity reverses alcohol-induced acetylation [147][148][149][150][151][152]. The pathogenesis and progression of ALD is thought to occur through several mechanisms including oxidative stress, inflammation, and mitochondrial dysfunction.…”