title: Tryptophan metabolism along the kynurenine pathway in diet-induced and genetic hypercholesterolemic rabbits.
abstract: BACKGROUND
  The activity of nicotinic acid in hypercholesterolemia has been poorly understood. In man, nicotinic acid derives for the most part from tryptophan along the tryptophan-nicotinic acid pathway, also called the kynurenine pathway, kynurenine being the key metabolite in this process. In the present paper, we investigated if, in animals with hypercolesterolemia, degradation of tryptophan to nicotinic acid along the kynurenine pathway was perturbated.
  
  
  METHODS
  Liver, kidney and intestine enzyme activities of the tryptophan-nicotinic acid pathway in normolipidemic, diet-induced hyperlipidemic New Zealand and heritable hypercholesterolemic Watanabe (WHHL) rabbits were determined.
  
  
  RESULTS
  Liver tryptophan 2,3-dioxygenase (TDO) activity was present only as a holoenzyme and was higher in the controls than in the hyperlipidemic and Watanabe rabbits, but no difference was present between the group fed an atherogenic hyperlipidic diet and the WHHL rabbits. Small intestine indole 2,3-dioxygenase (IDO) did not vary significantly among the three groups but was higher in comparison with liver TDO activity. In liver, kynurenine 3-monooxygenase and kynurenine-oxoglutarate transaminase activities did not show any significant difference among the three groups of rabbits. Kynureninase and 3-hydroxyanthranilate 3,4-dioxygenase activities per g of fresh tissue decreased significantly in the group of hyperlipidemic and in WHHL rabbits. In the kidneys, kynurenine 3-monooxygenase and kynureninase activity did not change significantly in the three groups of rabbits; kynurenine-oxoglutarate transaminase activity per g of fresh tissue decreased in both hyperlipidemic groups, but no significant difference was observed between hyperlipidemic and Watanabe rabbits. 3-Hydroxyanthranilate 3,4-dioxygenase activity in kidney was decreased markedly in hyperlipidemic and Watanabe rabbits, but there was no difference between the two hypercholesterolemic groups. Aminocarboxymuconate-semialdehyde decarboxylase activity did not change. Thus 3-hydroxyanthranilate 3,4-dioxygenase may be an important regulatory mechanism in the control of the flow of tryptophan along the kynurenine pathway to NAD in hypercholesterolemic rabbits.
  
  
  CONCLUSIONS
  This study first demonstrates that in rabbits, hypercholesterolemia, both diet- or genetically induced, can influence the enzyme activities of the tryptophan-nicotinic acid pathway leading to a decreased formation of nicotinic acid, and thus NAD.
authors.affiliation: Department of Pharmaceutical Sciences, University of Padova, Via F. Marzolo 5, I-35131 Padova, Italy.
authors.forename: Graziella
authors.initials: G
authors.lastname: Allegri
authors.forename: Eugenio
authors.initials: E
authors.lastname: Ragazzi
authors.forename: Carlo V L
authors.initials: CV
authors.lastname: Costa
authors.forename: Laura
authors.initials: L
authors.lastname: Caparrotta
authors.forename: Monica
authors.initials: M
authors.lastname: Biasiolo
authors.forename: Stefano
authors.initials: S
authors.lastname: Comai
authors.forename: Antonella
authors.initials: A
authors.lastname: Bertazzo
mesh_terms: D000818:Animals; D002262:Carboxy-Lyases / Q000378:metabolism; D006937:Hypercholesterolemia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007421:Intestine, Small / Q000201:enzymology; D007668:Kidney / Q000201:enzymology; D007737:Kynurenine / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase; D008099:Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009525:Niacin / Q000378:metabolism; D011817:Rabbits; D000637:Transaminases / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000378:metabolism
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D009525:Niacin; D007737:Kynurenine; D014364:Tryptophan; D006899:Mixed Function Oxygenases; D014366:Tryptophan Oxygenase; D050601:Kynurenine 3-Monooxygenase; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase; D002262:Carboxy-Lyases; C024396:aminocarboxymuconate-semialdehyde decarboxylase