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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

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Abstract

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.

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Acknowledgments

We thank Dr. Ruben J. J. Ramos, Faculty of Pharmacy, Universidade de Lisboa (FFUL) for technical assistance.

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Authors and Affiliations

  1. Research Institute for Medicines – iMed.ULisboa, Metabolism and Genetics Group, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal

    Marco F. Moedas, Isabel Tavares de Almeida & Margarida F. B. Silva

  2. Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal

    Isabel Tavares de Almeida & Margarida F. B. Silva

  3. Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    Marco F. Moedas, Arno G. van Cruchten, Lodewijk IJlst, Wim Kulik & Ronald J. A. Wanders

  4. Centro de Desenvolvimento Luís Borges, Hospital Pediátrico de Coimbra, Coimbra, Portugal

    Luísa Diogo

Authors
  1. Marco F. Moedas
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  2. Arno G. van Cruchten
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  3. Lodewijk IJlst
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  4. Wim Kulik
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  5. Isabel Tavares de Almeida
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  6. Luísa Diogo
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  7. Ronald J. A. Wanders
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  8. Margarida F. B. Silva
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Correspondence to Margarida F. B. Silva.

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Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval for animal studies

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Ethical approval for human studies

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Funding

This study was supported by Fundação para a Ciência e a Tecnologia (FCT), Lisboa, Portugal, by a grant awarded to Marco F. Moedas (SFRH/BD/69062/2010).

Informed consent

Informed consent was obtained from the individual participants included in the study or their parents to use laboratory data.

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Ronald J. A. Wanders and Margarida F. B. Silva should be considered as equal last authors.

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Moedas, M.F., van Cruchten, A.G., IJlst, L. et al. 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. Metabolomics 12, 142 (2016). https://doi.org/10.1007/s11306-016-1091-9

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