{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T02:59:31Z","timestamp":1761101971274},"reference-count":29,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2011,12,22]],"date-time":"2011-12-22T00:00:00Z","timestamp":1324512000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BD\/25913\/2005"],"award-info":[{"award-number":["SFRH\/BD\/25913\/2005"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2012,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Valproic acid (VPA) is a widely used anticonvulsant drug which affects mitochondrial metabolism including the catabolism of fatty acids and branched\u2010chain amino acids.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aims<\/jats:title><jats:p>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\u2010methylcrotonyl\u2010CoA carboxylase (3MCC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Urine organic acid analysis was performed in patients under VPA therapy and healthy controls using gas\u2010chromatography\/mass spectrometry (GC\u2010MS). Biotinidase activity was determined in plasma samples of both groups using an optimized spectrophotometric assay. After immunoprecipitation of short\u2010chain enoyl\u2010CoA hydratase (crotonase, ECHS1), 3MCC activity was measured in human liver homogenate using high\u2010performance liquid chromatography (HPLC), in the absence and presence of valproyl\u2010CoA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The levels of 3\u2010hydroxyisovaleric acid (3OH\u2010IVA), 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\u2010methylcrotonyl\u2010CoA carboxylase by valproyl\u2010CoA (IC<jats:sub>50<\/jats:sub>\u2009=\u20091.36 mM). Furthermore, we show that after complete immunoprecipitation of crotonase in a human liver homogenate, 3\u2010hydroxyisovaleryl\u2010CoA is not formed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>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\u2010CoA 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\u2010treated patients.<\/jats:p><\/jats:sec>","DOI":"10.1007\/s10545-011-9423-4","type":"journal-article","created":{"date-parts":[[2011,12,21]],"date-time":"2011-12-21T07:22:20Z","timestamp":1324452140000},"page":"443-449","source":"Crossref","is-referenced-by-count":19,"title":["Inhibition of 3\u2010methylcrotonyl\u2010CoA carboxylase explains the increased excretion of 3\u2010hydroxyisovaleric acid in valproate\u2010treated patients"],"prefix":"10.1002","volume":"35","author":[{"given":"Paula B. M.","family":"Lu\u00eds","sequence":"first","affiliation":[{"name":"Research Institute for Medicines and Pharmaceutical Sciences, iMed.UL Faculdade de Farm\u00e1cia da Universidade de Lisboa Lisboa Portugal"}]},{"given":"Jos P.","family":"Ruiter","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Pediatrics Academic Medical Center Amsterdam, Meibergdreef 9 Amsterdam 1105 AZ The Netherlands"}]},{"given":"Lodewijk","family":"IJlst","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Pediatrics Academic Medical Center Amsterdam, Meibergdreef 9 Amsterdam 1105 AZ The Netherlands"}]},{"given":"Lu\u00edsa","family":"Diogo","sequence":"additional","affiliation":[{"name":"Centro de Desenvolvimento Lu\u00eds Borges Hospital Pedi\u00e1trico de Coimbra Coimbra Portugal"}]},{"given":"Paula","family":"Garcia","sequence":"additional","affiliation":[{"name":"Centro de Desenvolvimento Lu\u00eds Borges Hospital Pedi\u00e1trico de Coimbra Coimbra Portugal"}]},{"given":"Isabel Tavares","family":"de Almeida","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines and Pharmaceutical Sciences, iMed.UL Faculdade de Farm\u00e1cia da Universidade de Lisboa Lisboa Portugal"},{"name":"Department of Biochemistry and Human Biology Faculdade de Farm\u00e1cia da Universidade de Lisboa Av. Prof. Gama Pinto Lisboa 1649\u2010003 Portugal"}]},{"given":"Marinus","family":"Duran","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Pediatrics Academic Medical Center Amsterdam, Meibergdreef 9 Amsterdam 1105 AZ The Netherlands"}]},{"given":"Ronald J.","family":"Wanders","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Pediatrics Academic Medical Center Amsterdam, Meibergdreef 9 Amsterdam 1105 AZ The Netherlands"}]},{"given":"Margarida F. B.","family":"Silva","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines and Pharmaceutical Sciences, iMed.UL Faculdade de Farm\u00e1cia da Universidade de Lisboa Lisboa Portugal"},{"name":"Department of Biochemistry and Human Biology Faculdade de Farm\u00e1cia da Universidade de Lisboa Av. 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