title: 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.
abstract: OBJECTIVE
  The aims were to provide proofs of mechanism and principle by establishing the ability of kynurenine metabolites to inhibit the liver mitochondrial low K(m) 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.
authors: The Cardiff School of Health Sciences, University of Wales Institute Cardiff, Western Avenue, Cardiff, Wales, UK. abadawy@uwic.ac.uk
authors: Abdulla A-B
authors: AA
authors: Badawy
authors: Samina
authors: S
authors: Bano
authors: Alex
authors: A
authors: Steptoe
mesh_terms: D015095:3-Hydroxyanthranilic Acid / Q000008:administration & dosage / Q000494:pharmacology; D000079:Acetaldehyde / Q000097:blood; D000427:Alcohol Deterrents / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000517:prevention & control*; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D007736:Kynurenic Acid / Q000008:administration & dosage / Q000494:pharmacology; D007737:Kynurenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D055502:Secondary Prevention; D014364:Tryptophan / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000427:Alcohol Deterrents; D002492:Central Nervous System Depressants; D015095:3-Hydroxyanthranilic Acid; C005045:3-hydroxykynurenine; D007737:Kynurenine; D000431:Ethanol; D014364:Tryptophan; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde; D007736:Kynurenic Acid