Tryptophan metabolic pathway in pathology : an example in phenylketonuria and cardiovascular disease prospect ; Etude de la voie catabolique du tryptophane dans différentes conditions pathologiques : exemple de la phénylcétonurie et perspectives dans les maladies cardiovasculaires

Tryptophan (Trp) metabolism was investigated in various pathology, including cardiovascular diseases, cancerology and neurodegenerative diseases. Trp, an essential aminoacid, is catabolized into two major pathways: kynurenine (KYN) pathway represents 98% of Trp catabolism and is involved in cardiopathy and immune tolerance, as serotonin (5HT) pathway is implicated in depression and sleep. In this work, we have studied Trp pathway in phenylketonuria (PKU) and cardiovascular diseases.Firstly, we developed a simple method for quantification of Trp and 8 of its metabolites, involved in both KYN and 5HT pathways, using liquid chromatography coupled to tandem mass spectrometry. This method, with a quick chromatographic runtime (15 min) and simple sample preparation, has been validated according to NF EN ISO 15189 criteria.Secondly, we explored Trp metabolism in phenylketonuria (OMIM 261600), a pathology caused by deficiency of phenylalanine hydroxylase enzyme (EC 1.14.16.1), that catalyses hydroxylation of phenylalanine (Phe) to tyrosine. Early low-Phe diet treatment, results in the prevention of severe mental retardation (IQ < 50) seen in untreated PKU patients.Many similarities between Trp and Phe metabolisms exist: transporters, cofactor and chaperone enzyme, and inhibition of one pathway by metabolites of the other pathway. As some of these metabolites have neuroactive properties, they should be considered in neurological impairment seen in this pathology and not totally explained by blood Phe concentrations.We assessed here a change of Trp metabolism in 151 adult PKU patients, with diminution of plasmatic concentrations of KYN and 3-hydroxykynurenic acid (3HK) in PKU patients compared to general population (P < .0001). These modifications were modified by diet type.In third line, we evaluated Trp metabolism in cardiovascular diseases. Prevention of these diseases representes a serious public health issue, based on diminution of co-morbidities like obstructive sleep apnoea (OSA). This syndrome affects 6-17% ...