Comparison of effects of nicotinic acid or tryptophan on tryptophan 2,3-dioxygenase in acute and chronic studies

Tryptophan is one of the strongest activators of tryptophan 2,3-dioxygenase, the rate-limiting enzyme in the pathway which degrades tryptophan. One of the metabolites thus formed is nicotinic acid, widely administered as a drug--often at high doses--and a vitamin. This study determined whether nicotinic acid also has a potency to activate tryptophan 2,3-dioxygenase and, if so, by what mechanism, whether changes in plasma tryptophan result, and if such activation is permanent. The results showed that nicotinic acid activated the enzyme almost as strongly as tryptophan. The results confirmed the activation to be of the "substrate" type, i.e., at least partly due to increased tryptophan concentrations in the liver. In repeated nicotinic acid administration plasma tryptophan levels did not diminish, despite the high activation of tryptophan 2,3-dioxygenase (high flux of tryptophan through the kynurenine pathway). However, the activation disappeared after 11 days of treatment. The powerful and sustained activation of tryptophan 2,3-dioxygenase by nicotinic acid may at least partly explain some of its side effects, such as glucose intolerance. However, mental disturbance as a side effect of diminished brain levels of tryptophan is not supported by these findings.