These studies were designed to define the mechanism by which the tryptophan metabolite, quinolinic acid, blocks gluconeogenesis and to determine the role it plays in influencing this process under physiologic and pathologic conditions. An alteration in the level of gluconeogenic intermediates occurred at a quinolinic acid content of 43 ng. per gram of liver. At a content of 10 μug. per gram of liver there was no significant change in the level of these intermediates. The concentration of quinolinic acid (3.7 × 10−4 M) which was associated with inhibition of P-enolpyruvate carboxykinase in vivo correlated well with K1 (1 × 10−4 M) derived for ferrous quinolinate in vitro. This level of quinolinic acid was reached by the intraperitoneal administration of approximately one fourth and the intragastric administration of approximately one half the daily dietary intake of L-tryptophan. The content of quinolinic acid in the liver of fasted animals was twenty-five-fold lower than the level required to inhibit the carboxykinase reaction and there was no increase in the quinolinic acid content of the liver on a diet containing the usual amount of tryptophan. The effects of various parameters on the conversion of tryptophan to quinolinic acid were also investigated and the clinical implications of these findings are discussed.

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