title: Glucose metabolism and hemoglobin reactivity in human red blood cells exposed to the tryptophan metabolites 3-hydroxyanthranilate, quinolinate and picolinate.
abstract: Glucose metabolism and hemoglobin reactivity in intact human erythrocytes were assessed in the presence of the tryptophan metabolites, 3-hydroxyanthranilate (3-HAT), quinolinate and picolinate. Of these compounds, only 3-HAT altered red cell oxidative status by inducing, in a dose-dependent manner, formation of methemoglobin and non-functional oxidation products of hemoglobin, and by increasing both net glycolytic flux and flux through the hexose monophosphate shunt. 3-HAT also decreased the normal lactate to pyruvate production ratio with pyruvate accumulating at the expense of lactate. These findings are consistent with the auto-oxidative reactivity of quinolinate, picolinate, and 3-HAT in that only 3-HAT undergoes base-catalyzed auto-oxidation (Dykens et al., Biochem Pharmacol 36: 211-217, 1987). Lactate and pyruvate added to the medium in physiologic concentrations uncoupled oxidative glycolysis from reductive glycolysis, resulting in accumulation of pyruvate in the presence of 3-HAT with little increase in total glycolytic flux. Superoxide dismutase (SOD), which accelerates 3-HAT auto-oxidation in vitro (Dykens et al., Biochem Pharmacol 36: 211-217, 1987), exacerbated HAT-mediated oxidative insult by increasing methemoglobin formation, hexose monophosphate shunt flux, and pyruvate accumulation. Persistence of 3-HAT-induced red cell metabolic responses and oxidative damage in the presence of SOD, DETAPAC (diethylenetriaminepentaacetic acid) and formate suggests that an organic-based radical, perhaps the anthranilyl radical produced during 3-HAT auto-oxidation, is the proximate agent exerting oxidative stress. Slow rates of auto-oxidation indicate that 3-HAT may be useful as a probe of antioxidant mechanisms in normal and diseased red blood cells.
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York 10016.
authors.forename: J A
authors.initials: JA
authors.lastname: Dykens
authors.forename: S G
authors.initials: SG
authors.lastname: Sullivan
authors.forename: A
authors.initials: A
authors.lastname: Stern
mesh_terms: D015095:3-Hydroxyanthranilic Acid / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D005561:Formates / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D004369:Pentetic Acid / Q000494:pharmacology; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D010848:Picolinic Acids / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D005561:Formates; D006454:Hemoglobins; D010848:Picolinic Acids; D011725:Pyridines; D011805:Quinolinic Acids; D062367:ortho-Aminobenzoates; C030544:formic acid; D015095:3-Hydroxyanthranilic Acid; D004369:Pentetic Acid; D013482:Superoxide Dismutase; D017378:Quinolinic Acid; D005947:Glucose; C030614:picolinic acid