Transient decrease of hepatic NAD+ and amino acid alterations during treatment with valproate: new insights on drug-induced effects in vivo using targeted MS-based metabolomics
| Autor: | Margarida F. B. Silva, Lodewijk IJlst, Isabel Tavares de Almeida, Ronald J. A. Wanders, Arno van Cruchten, Luísa Diogo, Marco F. Moedas, Wim Kulik |
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| Přispěvatelé: | Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Genetic Metabolic Diseases |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Nicotinamide Endocrinology Diabetes and Metabolism Clinical Biochemistry Tryptophan Fatty acid Metabolism Pharmacology Biology Biochemistry Amino acid 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine chemistry Glycine NAD+ kinase 030217 neurology & neurosurgery Kynurenine |
| Zdroj: | Metabolomics, 12(8). Springer New York |
| ISSN: | 1573-3890 1573-3882 |
| DOI: | 10.1007/s11306-016-1091-9 |
| Popis: | Background Therapeutic administration of the drug valproate (VPA) results in metabolic changes at the hepatic level that have not been fully characterized. Interference of this branched-chain fatty acid with the oxidative metabolism of amino acids may have consequences for the downstream biosynthesis of essential cofactors. Objectives We aimed to evaluate the effect of VPA on amino acid and NAD(+) metabolism using targeted MS-based metabolite profiling. Methods Plasma samples from patients under chronic treatment with VPA were analyzed. VPA was administered to Wistar rats mimicking prolonged and acute treatment, the latter with two different doses. Plasma and liver samples were collected for targeted metabolomics studies using UPLC-MS/MS and GC-FID. Results Analysis of amino acids in rat plasma and liver and in human plasma demonstrated that drug intake is associated with a particularly significant drop in the levels of tryptophan, and increased levels of glycine and lysine. The lowered plasma tryptophan levels prompted us to study the intracellular content of tryptophan and various nicotinamide adenine dinucleotides. A significant decrease of NAD(+) and NADP(+) was observed in the liver of rats after the single administration of VPA at two different doses, but not after repeated administration. Conclusion The observed accumulation of kynurenine intermediates in rat liver tissue suggests a drug-induced interference with the de novo pathway of NAD(+) biosynthesis. These findings provide novel insights into the mechanisms of VPA associated hepatocellular dysfunction and/or toxicity, but with possible major relevance to the anticancer effects of the drug |
| Databáze: | OpenAIRE |
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