Tryptophan metabolism, disposition and utilization in pregnancy

Abstract

SynopsisTryptophan (Trp) requirements in pregnancy are several-fold: (1) the need for increased protein synthesis by mother and for fetal growth and development; (2) serotonin (5-HT) for signalling pathways; (3) kynurenic acid (KA) for neuronal protection; (4) quinolinic acid (QA) for NAD + synthesis (5) other kynurenines (Ks) for suppressing fetal rejection. These goals could not be achieved if maternal plasma [Trp] is depleted. Although plasma total (free + albuminbound) Trp is decreased in pregnancy, free Trp is elevated. The above requirements are best expressed in terms of a Trp utilization concept. Briefly, Trp is utilized as follows: (1) In early and mid-pregnancy, emphasis is on increased maternal Trp availability to meet the demand for protein synthesis and fetal development, most probably mediated by maternal liver Trp 2,3-dioxygenase (TDO) inhibition by progesterone and oestrogens. (2) In mid-and late pregnancy, Trp availability is maintained and enhanced by the release of albumin-bound Trp by albumin depletion and non-esterified fatty acid (NEFA) elevation, leading to increased flux of Trp down the K pathway to elevate immunosuppressive Ks. An excessive release of free Trp could undermine pregnancy by abolishing T-cell suppression by Ks. Detailed assessment of parameters of Trp metabolism and disposition and related measures (free and total Trp, albumin, NEFA, K and its metabolites and pro-and anti-inflammatory cytokines in maternal blood and, where appropriate, placental and fetal material) in normal and abnormal pregnancies may establish missing gaps in our knowledge of the Trp status in pregnancy and help identify appropriate intervention strategies.

Fetal growth‐retardation and brain‐sparing by malnutrition are associated to changes in neurotransmitters profile

“…The development of the fetuses with gestational age was accompanied by a higher synthesis and utilization of neurotransmitters, despite a similar availability of precursors which may reflect the increased fetal distress by malnutrition with time of pregnancy (Holden, 2007; Badawy, 2015). Most of the offspring coped with the situation but the fetuses affected by growth‐retardation evidenced altered neurotransmitters pathways at both catecholamines and indoleamines systems.…”

Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice

“…In addition, the present study revealed several unexpected, tissue-specific metabolic features and other previously unrecognized downstream effects of TDO and IDO elimination. These effects shed new light on the regulation of the KP, which metabolizes the vast majority of dietary tryptophan in mammals (50), and have added relevance due to the fact that a number of KP metabolites have distinct, biologically significant properties (14,51–53). Notably, we found no evidence that IDO can substitute for TDO in the absence of the latter or, conversely, that TDO performs IDO-like functions in Ido −/− mice.…”

Restraint Stress during Pregnancy Rapidly Raises Kynurenic Acid Levels in Mouse Placenta and Fetal Brain

“…TRP levels are also raised in the fetal brain when pregnant rats are stressed by crowding during the final week of gestation [38], though, to our knowledge, this effect has so far not been authenticated in mice. Although the underlying mechanism(s) may also include compensatory down-regulation of other TRP-degrading placental enzymes during the prenatal period [39] and/or direct effects of steroid hormones on TRP metabolism [40–42], the elevated TRP levels seen in the highly vascularized placenta [43] immediately after restraint of the dam were more likely related to increased free TRP or to the presence of maternal blood where we observed a trend toward increased TRP levels (Table 2). …”

“…KP metabolites and enzymes, too, may play a role in the placenta both under physiological conditions and when the organ is compromised [32,50–53]. Notably, as both TRP and KYN pass easily from the placenta to the fetus [42,51,54,55], the transient increases in the fetal levels of these two compounds seen here in response to maternal stress may be at least in part caused by direct transfer from the placenta. KYNA, in contrast, does not penetrate readily from the placenta into the fetus [55], i.e.…”