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

Abstract

Aims: The aims were to provide proofs of mechanism and principle by establishing the ability of kynurenine metabolites to inhibit the liver mitochondrial low Km aldehyde dehydrogenase (ALDH) activity after administration and in vivo, and to induce aversion to alcohol. Methods: Kynurenic acid (KA), 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3-HAA) were administered to normal male Wistar rats and ALDH activity was determined both in vitro in liver homogenates and in vivo (by measuring blood acetaldehyde following ethanol administration). Alcohol consumption was studied in an aversion model in rats and in alcohol-preferring C57 mice. Results: ALDH activity was significantly inhibited by all three metabolites by doses as small as 1 mg/kg body wt. Blood acetaldehyde accumulation after ethanol administration was strongly elevated by KA and 3-HK and to a lesser extent by 3-HAA. All three metabolites induced aversion to alcohol in rats and decreased alcohol preference in mice. Conclusions: The above kynurenine metabolites of tryptophan induce aversion to alcohol by inhibiting ALDH activity. An intellectual property covering the use of 3-HK and 3-HAA and derivatives thereof in the treatment of alcoholism by aversion awaits further development.

Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application

“…Four tryptophan metabolites in the kynurenine pathway (3-hydroxykynurenine, 3-hydroxyanthranilic acid, kynurenic acid, and indol-3-ylpyruvic acid), have been shown to inhibit rat liver mitochondrial ALDH2 (Badawy and Morgan, 2007). These agents are being developed as potential antidipsotropic treatments (Badawy et al, 2011).…”

Tryptophan in Alcoholism Treatment II: Inhibition of the Rat Liver Mitochondrial Low Km Aldehyde Dehydrogenase Activity, Elevation of Blood Acetaldehyde Concentration and Induction of Aversion to Alcohol by Combined Administration of Tryptophan and Benserazide

“…All other chemicals and materials were purchased from this and the other sources listed in the preceding paper (Badawy et al ., 2011). …”

Elevation of Kynurenine Metabolites in Rat Liver and Serum: A Potential Additional Mechanism of the Alcohol Aversive and Anti-cancer Effects of Disulfiram?

“…1 ) to cause aversion to alcohol by inhibiting the rat liver mitochondrial low k m form of aldehyde dehydrogenase (ALDH: EC 1.2.1.3). Of these, 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA) and kynurenic acid (KA) were found to be potent inhibitors of the enzyme activity in vitro ( Badawy and Morgan, 2007 ) and after acute and chronic administration, and in vivo by elevating blood acetaldehyde concentration following acute ethanol administration ( Badawy et al , 2011a ). Alcohol aversion and ALDH inhibition after administration and in vivo were also observed in rats when hepatic [3-HK] was elevated by combined acute or chronic administration of Trp and the kynureninase inhibitor benserazide ( Badawy et al , 2011b ).…”