Oxidative reactivity of the tryptophan metabolites 3-hydroxyanthranilate, cinnabarinate, quinolinate and picolinate.
The oxidative reactivities of four tryptophan metabolites in the kynurenine pathway were examined as a potential mechanism for their reported neurotoxicities and carcinogenicities. Neither quinolinic acid, a neurotoxin, nor its monocarboxylic analogue, picolinic acid, auto-oxidized over a wide pH range. However, 3-hydroxyanthranilic acid (3-HAT), a carcinogen, readily auto-oxidized and the reaction rate increased exponentially with increasing pH. 3-HAT auto-oxidation likely involves two steps: auto-oxidation of 3-HAT to the semiquinoneimine (anthranilyl radical) which oxidizes to the quinoneimine, followed by condensation and oxidation reactions to yield a second carcinogen, cinnabarinic acid. 3-HAT auto-oxidation to cinnabarinate required molecular oxygen and generated superoxide radicals and H2O2. Superoxide dismutase (SOD) accelerated 3-HAT auto-oxidation 4-fold, probably by preventing back reactions between superoxide and either the anthranilyl radical or the quinoneimine formed during the initial step of auto-oxidation. Catalase did not accelerate 3-HAT auto-oxidation, but it did prevent destruction of cinnabarinate by H2O2. Interconversion between oxyhemoglobin and methemoglobin occurred during 3-HAT auto-oxidation, although neither form of hemoglobin altered rates of 3-HAT auto-oxidation. Mn2+, Mn3+ and Fe3+-EDTA did not directly catalyze cinnabarinate formation in the absence of O2, but they did accelerate cinnabarinate formation under aerobic conditions.
D015095:3-Hydroxyanthranilic Acid; D002374:Catalase / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D010078:Oxazines; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010848:Picolinic Acids; D011725:Pyridines; D017378:Quinolinic Acid; D011805:Quinolinic Acids; D013482:Superoxide Dismutase / Q000378:metabolism; D014364:Tryptophan; D062367:ortho-Aminobenzoates
D010078:Oxazines; D010848:Picolinic Acids; D011725:Pyridines; D011805:Quinolinic Acids; D062367:ortho-Aminobenzoates; D015095:3-Hydroxyanthranilic Acid; C000483:cinnabarinic acid; D014364:Tryptophan; D002374:Catalase; D013482:Superoxide Dismutase; D017378:Quinolinic Acid; C030614:picolinic acid