Tryptophan metabolites as potent inhibitors of aldehyde dehydrogenase activity and potential alcoholism-aversion therapeutic agents

Abstract

Alcoholism aversion therapy involves administration of a drug which inhibits the activity of the liver mitochondrial (or low K_m) enzyme aldehyde dehydrogenase (AlDH; EC 1. 2.1.3), so that if a person consumes alcohol while on such medication, s/he will experience the unpleasant symptoms and effects of acetaldehyde. Our work on the tryptophan (Trp) and serotonin status of patients with the chronic fatigue syndrome and observations of alcohol consumption behaviour of such patients led us to identify 4 Trp metabolites as potent inhibitors of AlDH activity from both yeast and rat liver mitochondria. Three of these inhibitors are kynurenine metabolites [3-hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HAA), and kynurenic acid (KA)], whereas the fourth is the Trp transamination product indol-3-ylpyruvic acid (IPA). At a range of concentrations of 2–100 μM, the 4 metabolites caused inhibition of the mammalian liver mitochondrial enzyme activity similar to or stronger than that produced by the classical AlDH inhibitor disulfiram. For example, at 2 μM, inhibition was 55, 46, 40 and 30% respectively, against 42% by disulfiram. We propose these Trp metabolites as potential alcoholism-aversion therapeutic agents. Our preferred strategy is to ensure accumulation of adequate concentrations of these AlDH-inhibitory metabolites by administration of Trp with metabolic blockade of the kynurenine pathway at the kynureninase step. Advantages of this new therapy over existing aversion drugs and of the proposed strategy are the following: (1) a much greater safety profile; (2) production at the required site of action (the liver); (3) decreased neuronal hyperexcitability (an important determinant of relapse by detoxified alcoholics) by the cytoprotective kynurenic acid and (4) by the decreased formation of the neurotoxin quinolinic acid by kynureninase inhibition; (5) provision of serotonin from Trp, thus counteracting the other important determinants of relapse, namely anxiety and depression. Our proposed therapy, which enjoys intellectual property protection, represents a novel, comprehensive and unique concept in alcoholism treatment, which merits clinical development.