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Inhibition of 3-methylcrotonyl-CoA carboxylase explains the increased excretion of 3-hydroxyisovaleric acid in valproate-treated patients.
MedLine Citation:
PMID:  22189597     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND: Valproic acid (VPA) is a widely used anticonvulsant drug which affects mitochondrial metabolism including the catabolism of fatty acids and branched-chain amino acids. AIMS: To 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). METHODS: Urine 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. RESULTS: The 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.
Authors:
Paula B M Luís; Jos P Ruiter; Lodewijk Ijlst; Luísa Diogo; Paula Garcia; Isabel Tavares de Almeida; Marinus Duran; Ronald J Wanders; Margarida F B Silva
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-12-22
Journal Detail:
Title:  Journal of inherited metabolic disease     Volume:  -     ISSN:  1573-2665     ISO Abbreviation:  -     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7910918     Medline TA:  J Inherit Metab Dis     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Research Institute for Medicines and Pharmaceutical Sciences, iMed.UL, Faculdade de Farmácia da Universidade de Lisboa, Lisboa, Portugal.
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