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1.  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 
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.
doi:10.1093/alcalc/agr134
PMCID: PMC3196366  PMID: 21896552
2.  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 
Aims: The aims were to provide proofs of mechanism and principle by establishing the ability of the amino acid L-tryptophan (Trp) combined with the kynureninase inhibitor benserazide (BSZ) to inhibit the liver mitochondrial low Km aldehyde dehydrogenase (ALDH) activity after administration and in vivo and to induce aversion to alcohol. Methods: Trp, BSZ or both were administered to male Wistar rats and ALDH activity was determined both in vitro in liver homogenates and in vivo (by measuring acetaldehyde accumulation in blood after ethanol administration). Alcohol consumption was studied in an aversion model in rats and in alcohol-preferring C57 mice. Results: Combined administration of Trp + BSZ, but neither compound alone, produced a strong inhibition of ALDH activity and an increase in blood acetaldehyde concentration after ethanol, and induced aversion to alcohol in rats and decreased preference in mice. Another kynureninase inhibitor, carbidopa, induced aversion to alcohol by itself, which was reversed by Trp co-administration. Conclusions: The present results establish a prior art for the use of a combination of Trp plus BSZ in the treatment of alcoholism by aversion, which merits rapid clinical development.
doi:10.1093/alcalc/agr135
PMCID: PMC3196367  PMID: 21896551
3.  Activation of Liver Tryptophan Pyrrolase Mediates the Decrease in Tryptophan Availability to the Brain after Acute Alcohol Consumption by Normal Subjects 
Aims: We have previously suggested that acute ethanol consumption by normal subjects decreases the availability of circulating tryptophan (Trp) to the brain by activating liver Trp pyrrolase, the first and rate-limiting enzyme of the (major) kynurenine pathway of Trp degradation. The aim of the present study was to examine this hypothesis further by measuring plasma levels of kynurenine metabolites following alcohol consumption. Methods: After an overnight fast and a light breakfast, each of 10 healthy subjects received one of five drinks (placebo and doses of ethanol of 0.2, 0.4, 0.6 and 0.8 g/kg body weight in tonic water) on five different occasions. Blood samples were withdrawn 2 h later and plasma was analysed for concentrations Trp, competing amino acids (CAA) and kynurenine metabolites. Results: Along with the depletion of plasma Trp and the decrease in its availability to the brain, as expressed by the ratio of [Trp]/[CAA], plasma kynurenine was elevated by doses of ethanol of 0.2–0.8 g/kg body weight. The ratio% of [kynurenine]/[Trp], an index of the expression of Trp pyrrolase activity, was also increased by all doses of ethanol. Conclusions: We conclude that activation of liver Trp pyrrolase mediates the depletion of plasma Trp and the decrease in its availability to the brain induced by acute ethanol consumption.
doi:10.1093/alcalc/agp005
PMCID: PMC2720730  PMID: 19201692

Results 1-3 (3)