Inhibition of 3-Methylcrotonyl-CoA Carboxylase Explains the Increased Excretion of 3-Hydroxyisovaleric Acid in Valproate-Treated Patients

    Paula B. Luis, J. P. N. Ruiter, Lodewijk IJlst, Luísa Diogo, Paula García, Isabel Tavares de Almeida, Marinus Durán, Ronald J. A. Wanders, Margarida F. B. Silva
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    TLDR Valproic acid treatment increases a specific acid in urine by blocking an enzyme, possibly causing skin rash and hair loss.
    The study investigated the impact of valproic acid (VPA), an anticonvulsant drug, on mitochondrial metabolism, specifically the leucine pathway, by comparing urine samples from VPA-treated patients to those from healthy controls using gas-chromatography/mass spectrometry. It was found that 3-hydroxyisovaleric acid levels were significantly higher in the urine of patients treated with VPA. Additionally, biotinidase activity in plasma samples showed a range from very low to normal in treated patients compared to controls. The study also demonstrated that valproyl-CoA, a metabolite of VPA, directly inhibits the activity of 3-methylcrotonyl-CoA carboxylase (3MCC) with an IC(50) of 1.36 mM. The inhibition of 3MCC and biotinidase by VPA and its metabolites may contribute to the side effects of skin rash and hair loss often reported by patients undergoing VPA treatment.
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