ArticleJournal of inherited metabolic disease2012
Inhibition of 3-methylcrotonyl-CoA carboxylase explains the increased excretion of 3-hydroxyisovaleric acid in valproate-treated patients.
Article in Journal of inherited metabolic disease, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers, 2 of them syntheses that pooled it.
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Who cites it
8 citing papers in PubMed, 2 syntheses or guidelines pooled it, 23 citations in OpenAlex.
- Metabolome panels as potential noninvasive biomarkers for primary glomerulonephritis sub-types: meta-analysis of profiling metabolomics studies.Scientific reports · 2023Pooled it
- Laboratory analysis of organic acids, 2018 update: a technical standard of the American College of Medical Genetics and Genomics (ACMG).Genetics in medicine : official journal of the American College of Medical Genetics · 2018Guideline
- The metabolic consequences of HIV/TB co-infection.BMC infectious diseases · 2023Article
- Predicting Valproate-Induced Liver Injury Using Metabolomic Analysis of Ex Ovo Chick Embryo Allantoic Fluid.Metabolites · 2023Article
- Dihydrolipoamide dehydrogenase, pyruvate oxidation, and acetylation-dependent mechanisms intersecting drug iatrogenesis.Cellular and molecular life sciences : CMLS · 2021Review
- Suspect screening and targeted analysis of acyl coenzyme A thioesters in bacterial cultures using a high-resolution tribrid mass spectrometer.Analytical and bioanalytical chemistry · 2021Article
- A (14)C-leucine absorption, distribution, metabolism and excretion (ADME) study in adult Sprague-Dawley rat reveals β-hydroxy-β-methylbutyrate as a metabolite.Amino acids · 2015Article
- Valproyl-CoA inhibits the activity of ATP- and GTP-dependent succinate:CoA ligases.Journal of inherited metabolic disease · 2014Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundValproic acid (VPA) is a widely used anticonvulsant drug which affects mitochondrial metabolism including the catabolism of fatty acids and branched-chain amino acids.
aimsTo elucidate the effect of valproate on the leucine pathway through a targeted metabolomics approach and the evaluation of the effects of valproate on the activity of biotinidase and 3-methylcrotonyl-CoA carboxylase (3MCC).
methodsUrine organic acid analysis was performed in patients under VPA therapy and healthy controls using gas-chromatography/mass spectrometry (GC-MS). Biotinidase activity was determined in plasma samples of both groups using an optimized spectrophotometric assay. After immunoprecipitation of short-chain enoyl-CoA hydratase (crotonase, ECHS1), 3MCC activity was measured in human liver homogenate using high-performance liquid chromatography (HPLC), in the absence and presence of valproyl-CoA.
resultsThe levels of 3-hydroxyisovaleric acid (3OH-IVA), one secondary metabolite of the leucine pathway, were significantly elevated in human urine after VPA treatment. Biotinidase activity in plasma samples ranged from very low to normal levels in treated patients as compared with controls. Enzyme activity measurements revealed inhibition of 3-methylcrotonyl-CoA carboxylase by valproyl-CoA (IC(50) = 1.36 mM). Furthermore, we show that after complete immunoprecipitation of crotonase in a human liver homogenate, 3-hydroxyisovaleryl-CoA is not formed. DISCUSSION: Our results suggest the interference of VPA with the activity of 3MCC through a potential cumulative effect: direct inhibition of the enzyme activity by the drug metabolite valproyl-CoA and the inhibition of biotinidase by valproate and/or its metabolites. These interactions may be associated with the skin rash and hair loss which are side effects often reported in VPA-treated patients.
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