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

Abdulla A.-B Badawy,Samina Bano

doi:10.1093/alcalc/agv085

Abstract

AimsThe tryptophan metabolites 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3-HAA) inhibit the liver mitochondrial low Km aldehyde dehydrogenase and possess alcohol-aversive and immunosuppressant properties. As the disulfiram (DS) metabolite carbon disulphide activates enzymes forming 3-HK and 3-HAA, we investigated if repeated disulfiram treatment increases the hepatic and serum levels of these 2 metabolites.MethodsLivers and sera of male Wistar rats were analysed for tryptophan and kynurenine metabolites after repeated DS treatment for 7 days.ResultsDS increased liver and serum [3-HK] and [3-HAA] possibly by increasing the flux of tryptophan down the hepatic kynurenine pathway and activation of kynurenine hydroxylase and kynureninase.ConclusionsWe provisionally suggest that elevation of some kynurenine metabolites may be an additional mechanism of the alcohol-aversive and anticancer effects of disulfiram.

Highlights

We have previously demonstrated the ability of some metabolites of the essential amino acid L-tryptophan (Trp) of the kynurenine (K) pathway (KP) (Fig. 1) to cause aversion to alcohol by inhibiting the rat liver mitochondrial low km form of aldehyde dehydrogenase (ALDH: EC 1.2.1.3)
In the context of ALDH-inhibitory kynurenine metabolites, it has been reported that the DS metabolite carbon disulphide (CS2) administered in doses of 200–800 ppm in air in an inhalation chamber stimulates the activities of K hydroxylase and kynureninase in rat kidney and/or liver (Okayama et al, 1988)
The present results have provided evidence for modulation of the hepatic kynurenine pathway by disulfiram, possibly via its carbon disulphide metabolite

Summary

Introduction

We have previously demonstrated the ability of some metabolites of the essential amino acid L-tryptophan (Trp) of the kynurenine (K) pathway (KP) (Fig. 1) to cause aversion to alcohol by inhibiting the rat liver mitochondrial low km form of aldehyde dehydrogenase (ALDH: EC 1.2.1.3). In the context of ALDH-inhibitory kynurenine metabolites, it has been reported that the DS metabolite carbon disulphide (CS2) administered in doses of 200–800 ppm in air in an inhalation chamber stimulates the activities of K hydroxylase and kynureninase in rat kidney and/or liver (Okayama et al, 1988). This would be expected to raise the hepatic concentrations of 3-HK and 3-HAA and, CS2, which is used in the viscose industry, is known (Freundt et al, 1976) to increase rat blood acetaldehyde concentration following acute ethanol administration, suggesting that it may inhibit ALDH activity, possibly by elevating K metabolites. It was considered of interest to examine the potential effect of repeated DS treatment of rats on the hepatic and serum concentrations of Trp, K and its metabolites

Methods

Results

Discussion

Conclusion