Effects of Tryptophan 2,3-Dioxygenase Inhibitors in the Rat
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Tryptophan is an essential amino acid and is therefore, under normal conditions, only supplied net from the diet (see Fig. 1). Although tryptophan is metabolized through several pathways in the body, it is thought that the catabolism of tryptophan in the liver through the kynurenine pathway is of greatest quanitative significance (Young et al., 1978). However, under certain conditions, enzymes which control other pathways elsewhere in the body, such as indoleamine 2,3-dioxygenase, are induced to such an extent that their respective pathways become quantitatively significant (Brown et al., 1987; Knowles et al., 1989). Under normal conditions, the concentration of tryptophan in the blood will be regulated by the activity of the kynurenine pathway of the liver (Knowles et al., 1989) because there is little regulation of dietary input of tryptophan, apart from substrate supply. Until recently, it has been thought that the activity of the kynurenine pathway of the liver is controlled exclusively by its first step, tryptophan 2,3-dioxygenase (TDO); however, studies with isolated liver cells have shown that significant control resides in the transport of the amino acid across the plasma membrane (Salter et al., 1985; Salter et al., 1986a). Upon induction of TDO, control moves from TDO to transport until transport becomes the major controlling step in the pathway (Salter et al., 1986a). Tryptophan is transported across the liver plasma membrane by two transport systems, systems L and T (Salter et al., 1986b). Because these systems are not subject to regulation, apart from competition effects of other amino acids (Salter et al., 1986b), changes in plasma tryptophan will usually be caused by changes in TDO activity.
KeywordsAromatic Amino Acid Kynurenine Pathway Liver Plasma Membrane Tryptophan Metabolism Serotonergic Function
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