Tryptophan metabolism in alcoholism

Abstract

Acute and chronic alcohol (ethanol) intake and subsequent withdrawal exert major effects on tryptophan (Trp) metabolism and disposition in human subjects and experimental animals. In rats, activity of the ratelimiting enzyme of Trp degradation, liver Trp pyrrolase (TP), is enhanced by acute, but inhibited after chronic, ethanol administration, then enhanced during withdrawal. These changes lead to alterations in brain serotonin synthesis and turnover mediated by corresponding changes in circulating Trp availability to the brain. A low brain-serotonin concentration characterizes the alcohol-preferring C57BL/6J mouse strain and many alcoholpreferring rat lines. In this mouse strain, liver TP enhancement causes the serotonin decrease. In man, acute ethanol intake inhibits brain serotonin synthesis by activating liver TP. This may explain alcohol-induced depression, aggression and loss of control in susceptible individuals. Chronic alcohol intake in dependent subjects may be associated with liver TP inhibition and a consequent enhancement of brain serotonin synthesis, whereas subsequent withdrawal may induce the opposite effects. The excitotoxic Trp metabolite quinolinate may play a role in the behavioural disturbances of the alcohol-withdrawal syndrome. Some abstinent alcoholics may have a central serotonin deficiency, which they correct by liver TP inhibition through drinking. Further studies of the Trp and serotonin metabolic status in long-term abstinence in general and in relation to personality characteristics, alcoholism typology and genetic factors in particular may yield important information which should facilitate the development of more effective screening, and preventative and therapeutic strategies in this area of mental health.

The tryptophan utilization concept in pregnancy

“…The bulk of dietary Trp is metabolized via 4 pathways, the quantitatively most important of which is the hepatic kynurenine-nicotinic acid pathway, accounting for >95% of Trp metabolism [1,2]. This pathway is controlled by the first enzyme, Trp 2,3-dioxygenase (TDO, formerly Trp pyrrolase) [1,2].…”

“…The bulk of dietary Trp is metabolized via 4 pathways, the quantitatively most important of which is the hepatic kynurenine-nicotinic acid pathway, accounting for >95% of Trp metabolism [1,2]. This pathway is controlled by the first enzyme, Trp 2,3-dioxygenase (TDO, formerly Trp pyrrolase) [1,2]. TDO is regulated by glucocorticoid induction involving de novo enzyme synthesis, substrate activation and stabilization by Trp, cofactor activation by heme and feedback inhibition by NAD(P)H [1,2].…”

“…This pathway is controlled by the first enzyme, Trp 2,3-dioxygenase (TDO, formerly Trp pyrrolase) [1,2]. TDO is regulated by glucocorticoid induction involving de novo enzyme synthesis, substrate activation and stabilization by Trp, cofactor activation by heme and feedback inhibition by NAD(P)H [1,2]. TDO activity can also be inhibited by estrogens and progesterone and this is of particular relevance to Trp disposition in pregnancy [3].…”

L-Tryptophan: Basic Metabolic Functions, Behavioral Research and Therapeutic Indications

“…This decrease suggests that brain serotonin synthesis is impaired under these conditions 87,89. Where the average individual is likely to tolerate this level of serotonin depletion without undue effects on their behavior, vulnerable individuals may experience a larger depletion effect (e.g.…”

“…50% or more) 90,91. This vulnerability may be due to a pre-existing condition of low or borderline serotonin function that could be further impaired by the diminished serotonin synthesis following acute alcohol consumption 88,89…”