“…This could occur by the reversible transamination reaction of the mammalian enzyme [55], or of the common gut firmicute Clostridium sporogenes [57]. Synthesis of Trp from IPA was suggested in a study of a healthy woman who restored her nitrogen balance by intake of IPA while being maintained on a synthetic Trp-free diet [58].…”
Section: The Transamination or Indolepyruvic Acid Pathwaymentioning
The essential amino acid
L
-tryptophan (Trp) undergoes
extensive metabolism along several pathways, resulting in production of many
biologically active metabolites which exert profound effects on physiological
processes. The disturbance in Trp metabolism and disposition in many disease
states provides a basis for exploring multiple targets for pharmaco-therapeutic
interventions. In particular, the kynurenine pathway of Trp degradation is
currently at the forefront of immunological research and immunotherapy. In this
review, I shall consider mammalian Trp metabolism in health and disease and
outline the intervention targets. It is hoped that this account will provide a
stimulus for pharmacologists and others to conduct further studies in this rich
area of biomedical research and therapeutics.
“…This could occur by the reversible transamination reaction of the mammalian enzyme [55], or of the common gut firmicute Clostridium sporogenes [57]. Synthesis of Trp from IPA was suggested in a study of a healthy woman who restored her nitrogen balance by intake of IPA while being maintained on a synthetic Trp-free diet [58].…”
Section: The Transamination or Indolepyruvic Acid Pathwaymentioning
The essential amino acid
L
-tryptophan (Trp) undergoes
extensive metabolism along several pathways, resulting in production of many
biologically active metabolites which exert profound effects on physiological
processes. The disturbance in Trp metabolism and disposition in many disease
states provides a basis for exploring multiple targets for pharmaco-therapeutic
interventions. In particular, the kynurenine pathway of Trp degradation is
currently at the forefront of immunological research and immunotherapy. In this
review, I shall consider mammalian Trp metabolism in health and disease and
outline the intervention targets. It is hoped that this account will provide a
stimulus for pharmacologists and others to conduct further studies in this rich
area of biomedical research and therapeutics.
“…In the present paper, we demonstrate the ability of the former three kynurenine metabolites to: (a) inhibit ALDH activity after administration to rats; (b) elevate blood acetaldehyde concentration following acute ethanol administration; (c) induce aversion to alcohol in an experimental aversion model and (d) decrease alcohol preference in mice, and propose these metabolites as potential alcohol aversion drugs. The Trp transamination metabolite IPA was not included in the present work because of its back-conversion into Trp (Richards et al ., 1972). Fig.…”
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.
“…Maintenance of nitrogen balance when the appropriate analogues were added to a diet lacking one or more essential amino acids has provided cir cumstantial evidence of transamination in man of the cp-keto acid analogues of phenylalanine, valine, leucine, isoleucine, tryptophan, methionine and histidine in health and uraemia (Gallina, Dominguez, Hoschoian & Barrio, 1971;Richards, Brown, Houghton & Thompson, 1971;Rudman, 1971;Richards, Brown & Lowe, 1972;Walser, Coulter, Dighe & Crantz, 1973). Hydroxy acids of 589 590 P. Richards methionine (Mitch & Walser, 1977a) and phenylalanine (Mitch & Walser, 1977b) have also more or less maintained nitrogen balance.…”
Section: Synthesis Of Essential Amino Acids In Manmentioning
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