Inhibition of hepatic tryptophan-2,3-dioxygenase: Superior potency of melatonin over serotonin

In view of the biogenic amine deficiency hypothesis of depression and the contentious claim that hepatic tryptophan‐2,3‐dioxygenase (TDO) is the major peripheral determinant of brain tryptophan, brain serotonin (5‐HT), and ultimately melatonin, the regulation of TDO by melatonin and 5‐HT is investigated and discussed. It is concluded that TDO activity is regulated differentially by melatonin and 5‐HT. Melatonin is a competitive inhibitor of TDO and 5‐HT is predominantly an allosteric inhibitor. In the presence of 5‐HT the effects of melatonin are nullified. However melatonin alone is a more potent inhibitor of TDO. Melatonin is also shown to be a reversible negative effector of TDO.