Tryptophan Metabolism and the Hepatic Kynurenine Pathway in Health and Disease

Abstract

Tryptophan (TRP) metabolism and disposition are reviewed with particular emphasis on the hepatic kynurenine pathway (HKP) in health and disease. Over 95 % of dietary TRP is metabolized in the HKP, which is controlled mainly by tryptophan 2,3-dioxygenase (TDO) and produces important metabolites affecting functions in the brain and periphery. TDO is regulated by glucocorticoids, the substrate TRP, and the cofactor heme and by feedback inhibition by reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H). TDO activity determines the rate of TRP degradation and hence its availability and that of its kynurenine (KYN) metabolites for various functions. TDO controls synthesis of heme in liver and serotonin (5-HT) in brain. TDO plays a central role in alcoholism, which exerts multiple effects on the HKP. The 5-HT deficiency in major depressive disorder (MDD) is due to a high TDO activity and antidepressant drugs act in part as TDO inhibitors. Only the HKP contains all the necessary enzymes for nicotinamide adenine dinucleotide (NAD+) synthesis and so plays the central role in pellagra. Criteria for assessing TRP oxidation are proposed. TDO may play a central role in the hepatic porphyrias by utilizing the regulatory heme pool. Maternal TRP availability is enhanced throughout pregnancy by TDO inhibition and altered TRP disposition. Immune activation does not play a role in TRP disposition during pregnancy nor in the 5-HT deficiency in MDD. Liver TDO inhibition is a potential strategy for treatment of depression, hepatic porphyrias, and cancer in view of emerging evidence of the role of TDO in cancer biology.