Tryptophan-Kynurenine Metabolism as a Common Mediator of Genetic and Environmental Impacts in Major Depressive Disorder: The Serotonin Hypothesis Revisited 40 Years Later

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ABSTRACT

The original 1969 Lancet paper proposed, "in depression the activity of liver tryptophan-pyrrolase is stimulated by raised blood corticosteroids levels, and metabolism of tryptophan is shunted away from serotonin production, and towards kynurenine production." Discovery of neurotropic activity of kynurenines suggested that up-regulation of the tryptophan-kynurenine pathway not only augmented serotonin deficiency but also underlined depressionassociated anxiety, psychosis and cognitive decline.

The present review of genetic and hormonal factors regulating kynurenine pathway of tryptophan metabolism suggests that this pathway mediates both genetic and environmental mechanisms of depression. Rate-limiting enzymes of kynurenine formation, tryptophan 2,3-dioxygenase (TDO) and indoleamine 23-dioxygenase (I DO) are activated by stress hormones (TDO) and/or by pro-inflammatory cytokines (IDO). Simultaneous presence of high producersalleles of proinflammatory cytokines genes (e.g., interf eron-gamma and tumor necrosis factor-alpha) determines the genetic predisposition to depression via up-regulation of IDO while impact of environmental stresses is mediated via hormonal activation of TDO. Tryptophankynurenine pathway represents a major meeting point of gene-environment interaction in depression and a new target for pharmacological intervention.

Although often referred to as "serotonin hypothesis," the 1969 Lancet paper proposed the disturbances of tryptophan (TRY) metabolism, i.e., the shunt of TRY from serotonin (5-HT) synthesis to kynurenine (KYN) formation, as a major etiological factor of depression (1). It suggested the formation of "vicious cycle" perpetuating the increase of KYN and decrease of 5-HT production in depression due to a) stress hormones - induced activation of tryptophan 2,3-dioxygenase (TDO), the rate-limiting enzyme of TRY - KYN pathway; b) diminished availability of TRY as an initial substrate of 5-HT biosynthesis due to increased formation of KYN from TRY; and c) increased production of Cortisol due to weakening of 5-HT inhibitory effect on amygdaloidal complex (2) (Fig. 1).

5-HT deficiency was thought as a major consequence of the shift of TRY metabolism to KYN formation, and "intensification of the central 5-HT-ergic processes" was suggested as "a possible determinant of the thymoleptic (mood-elevating) effect" (1). Introduction and wide use of selective 5-HT uptake inhibitors as antidepressant drugs contributed to almost 40 years of continued interest in the "serotonin hypothesis."

Another important consequence of so-called "serotonin hypothesis" was stimulation of research of biological and neurotropic activity of KYN and its derivatives (summarily called "kynurenines") (3-7) and of factors regulating KYN pathway of TRY metabolism (8). This review offers analysis of the current status of the serotonin hypothesis with special consideration of the discovery of indoleamine 2,3-dioxygenase (IDO) (9), the other rate-Umiting enzyme of TRY - KYN pathway, different from TDO in substrate specificity, localization and regulatory mechanisms.

TRYPTOPHAN METABOLISM

In humans TRY is an essential amino acid with two non-protein metabolic pathways: methoxyindoles and KYN (Fig. 2).

THE METHOXYINDOLES PATHWAY

Availability of TRY as a substrate is one of the ratelimiting factors of methoxyindoles pathway of 5-HT biosynthesis since less than 5% of TRY metabolized along this pathway (10). The other rate-limiting step is hydroxylation of TRY catalyzed by TRY-hydroxylase with the formation of 5-hydroxytryptophan. The subsequent decarboxylation results in the formation of 5-HT, a substrate for melatonin synthesis. The rate-Umiting step of melatonin synthesis is 5-HT-N-acetylation resulting in the formation of N-acetyl-serotonin (NAS) with subsequent O-methylation into 5-methoxy-Nacetyltryptamine (melatonin) (11) (Fig. 2).

5-HT (not competitively) and NAS and melatonin (competitively) inhibit liver TDO (12). …