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
Abstract: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 accumu… Show more
“…10 Aversion to alcohol by the same mechanism and mediated by 3-HK was also demonstrated by combined administration of Trp and the kynureninase inhibitor benserazide (BSZ). 11 In these latter two studies, hepatic levels of KA, 3-HK, and 3-HAA were reported after their administration, 10 as was 3-HK after administration of BSZ or the other kynureninase inhibitor carbidopa (CBD) in combination with Trp. 11 In the present paper, we report the effects of the above three kynurenine metabolites, and also BSZ, CBD, and Trp, on hepatic Trp metabolism by the KP.…”
Rat liver tryptophan (Trp), kynurenine pathway metabolites, and enzymes deduced from product/substrate ratios were assessed following acute and/or chronic administration of kynurenic acid (KA), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), Trp, and the kynureni-nase inhibitors benserazide (BSZ) and carbidopa (CBD). KA activated Trp 2,3-dioxygenase (TDO), possibly by increasing liver 3-HAA, but inhibited kynurenine aminotransferase (KAT) and kynureninase activities with 3-HK as substrate. 3-HK inhibited kynureninase activity from 3-HK. 3-HAA stimulated TDO, but inhibited kynureninase activity from K and 3-HK. Trp (50 mg/kg) increased kynurenine metabolite concentrations and KAT from K, and exerted a temporary stimulation of TDO. The kynureninase inhibitors BSZ and CBD also inhibited KAT, but stimulated TDO. BSZ abolished or strongly inhibited the Trp-induced increases in liver Trp and kynurenine metabolites. The potential effects of these changes in conditions of immune activation, schizophrenia, and other disease states are discussed.
“…10 Aversion to alcohol by the same mechanism and mediated by 3-HK was also demonstrated by combined administration of Trp and the kynureninase inhibitor benserazide (BSZ). 11 In these latter two studies, hepatic levels of KA, 3-HK, and 3-HAA were reported after their administration, 10 as was 3-HK after administration of BSZ or the other kynureninase inhibitor carbidopa (CBD) in combination with Trp. 11 In the present paper, we report the effects of the above three kynurenine metabolites, and also BSZ, CBD, and Trp, on hepatic Trp metabolism by the KP.…”
Rat liver tryptophan (Trp), kynurenine pathway metabolites, and enzymes deduced from product/substrate ratios were assessed following acute and/or chronic administration of kynurenic acid (KA), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), Trp, and the kynureni-nase inhibitors benserazide (BSZ) and carbidopa (CBD). KA activated Trp 2,3-dioxygenase (TDO), possibly by increasing liver 3-HAA, but inhibited kynurenine aminotransferase (KAT) and kynureninase activities with 3-HK as substrate. 3-HK inhibited kynureninase activity from 3-HK. 3-HAA stimulated TDO, but inhibited kynureninase activity from K and 3-HK. Trp (50 mg/kg) increased kynurenine metabolite concentrations and KAT from K, and exerted a temporary stimulation of TDO. The kynureninase inhibitors BSZ and CBD also inhibited KAT, but stimulated TDO. BSZ abolished or strongly inhibited the Trp-induced increases in liver Trp and kynurenine metabolites. The potential effects of these changes in conditions of immune activation, schizophrenia, and other disease states are discussed.
“…The relative contribution of the above K metabolites to the ALDH inhibition and anti-cancer effects of DS can be discerned in studies using specific inhibitors of K hydroxylase and kynureninase. The 3-HAA contribution could be studied using the kynureninase inhibitor benserazide, which has the additional advantage of inhibiting KAT activity, thereby preventing accumulation of KA (unpublished work; see also Badawy et al , 2011b ), which also inhibits ALDH activity ( Badawy et al , 2011a ). Using a K hydroxylase inhibitor, e.g.…”
Section: Discussionmentioning
confidence: 99%
“…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 ). Fig.…”
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.
“…Recently, the potential effects of various drugs on the hepatic metabolism of TRP have received more attention. Several studies have focused on the changes in the enzyme activity in the kynurenine pathway induced by some chemicals [1,2].…”
The levels of tryptophan (TRP) and its main metabolite kynurenic acid (KYNA) were measured in rat livers treated with raloxifene – a selective estrogen receptor modulator. The research was conducted by applying high-performance liquid chromatography on a 5 μm Zorbax Eclipse XDB-C18 column. Selective fluorescence detection (FL) was performed at an excitation of 219 nm and emission of 360 nm for TRP and KYNA. The assays showed good linearity (R2 >0.95) within the tested ranges of 0.045-0.20 µg mL−1, 0.025-0.32 µg mL−1, respectively, for KYNA and TRP. The limits of the detection were found to be 0.1480 ng mL−1 for KYNA and 0.0332 ng mL-1 for TRP. The deproteinization of the liver homogenate samples was accomplished by 80% methanol addition combined with boiling precipitation. The average recovery values were between 94.84% and 99.54% with RSDs no more than 5.5%. The work revealed that raloxifene decreased the mean value of tryptophan, as compared with the control group, while simultaneously leaving kynurenic acid at the same level. For the first time the research suggests that, in the case of raloxifene therapy, tryptophan is not metabolized via the kynurenine pathway.
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