An investigation into the antioxidative potential and regulatory aspects of liver tryptophan 2,3-dioxygenase by tryptophan and related analogues

Antunes, Ana Paula Martins (1998) An investigation into the antioxidative potential and regulatory aspects of liver tryptophan 2,3-dioxygenase by tryptophan and related analogues. Masters thesis, Rhodes University.

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Abstract

The amino acid, tryptophan, obtained through dietary means, is metabolised by the enzymes tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO) and tryptophan hydroxylase. All the enzymes have an effect on circulating tryptophan levels, especially TDO, since it is the major site of tryptophan catabolism in the liver and results in the production of kynurenine metabolites, viz. kynurenine, kynurenic acid, 3-hydroxyanthranilic acid and quinolinic acid. Extrahepatically, IDO is responsible for the synthesis of the kynurenine metabolites. Tryptophan 2,3-dioxygenase and IDO activity is increased by hormones or substrates such as tryptophan, and inflammation, in the case of IDO. Tryptophan availability for serotonin (5-HT) synthesis by the enzyme tryptophan hydroxylase is primarily dependent on TDO activity. A study was attempted in order to ascertain whether any of the endogenous metabolites of the kynurenine and serotonergic pathways would be able to inhibit TDO activity. Results showed that although the kynurenines had no effect, the indoleamines, except for the indoleacetic acids, were able to reduce TDO activity. 6-Methoxy-2-benzoxazolinone (6-MBOA), a structural analogue to melatonin, was the most potent inhibitor with a reduction in activity of 55 % compared with the control. The pineal gland in the rat brain has been shown to have the highest IDO activity. With induction, the kynurenine metabolite concentrations of kynurenic acid and quinolinic acid are increased. The effects of both compounds were determined on the serotonergic pathway. Although kynurenic acid produced no significant effect, quinolinic acid significantly reduced N-acetylserotonin and melatonin synthesis at concentrations of lOJLM and 100 JLM respectively. Many authors have implicated oxygen derived species as causative agents in the important neurodegenerative disorders such as Parkinson's and Huntington's disease. Increased radical generation and lipid peroxidation have been suggested to be responsible for the toxic destruction of neurons, especially in the brain because of its high lipid content and oxygen demand. The brain is therefore vulnerable to oxidative attack. During inflammatory diseases, IDO is induced with a resultant increase in kynurenines. This study was also an attempt at determining the effect of kynurenines on lipid peroxidation. All metabolites of the kynurenine pathway were able to induce lipid peroxidation significantly. The antioxidative potential of various tryptophan analogues, viz. serotonin, melatonin and 6-methoxy-2-benzoxazolinone, was determined using quinolinic acid-induced lipid peroxidation. Serotonin, melatonin and 6-MBOA were able to significantly reduce quinolinic acid-induced lipid peroxidation.

Item Type:Thesis (Masters)
Uncontrolled Keywords:Amino acid, Metabolism, Tryptophan 2,3-dioxygenase, TDO, Indoleamine 2,3-dioxygenase, IDO, Pineal gland, Rat brain, Oxygen, Parkinson's Disease, Huntington's Disease, Neurons, Antioxidative potential, Lipid peroxidation, Tryptophan hydroxylase, Catabolism, Liver, Kynurenine metabolites, Synthesis, Hormones, Serotonin, Endogenous metabolites
Subjects:Q Science > QD Chemistry > QD241 Organic chemistry > QD415 Biochemistry
T Technology > TP Chemical technology > Biotechnology
Divisions:Faculty > Faculty of Science > Biochemistry, Microbiology & Biotechnology
Supervisors:Daya, S
ID Code:3053
Deposited By: Philip Clarke
Deposited On:29 Jun 2012 06:06
Last Modified:29 Jun 2012 06:06
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