Abstract
VP is an eight carbon branched chain fatty acid. It is widely used as an anti-convulsant. Serious toxic side effects have occasionally been observed. VP is considered to be mainly metabolized via β-oxidation and glucuronide formation, and has been shown to inhibit fatty acid oxidation. However, the enzymatic mechanisms are currently unknown. We studied the VP-CoA oxidation by acyl-CoA dehydrogenases (ADs) and its inhibitory action on these enzymes using purified enzyme preparations. ADs catalyze the first reaction of the β-oxidation. Five of them are known. They are short (SCAD), medium (MCAD), long chain acyl-CoA dehydrogenases (LCAD), isovaleryl-CoA dehydrogenase (IVD) and 2-meBCAD. We purified all five of them to homogeneity from rat liver. We also purified SCAD, MCAD and IVD to homogeneity from human liver. Human LCAD was partially purified from placenta mitochondria. AD activities were assayed spectrophotometrically using phenazine methosulfate and dichloroindophenol (DCIP) as electron acceptors. Only 2-meBCAD dehydrogenated VP-CoA. The specific activity was 167 nmol of DCIP reduced/min/mg protein. This value was 7.6 percent of that for S-2-methylbutyryl-CoA, the best substrate for this enzyme. 2-Propyl-2-pentenoyl-CoA was identified as the reaction product by using GC/MS. No other ADs dehydrogenated VP-CoA to any significant degree. Inhibitory effects were tested using human Ads. 0.1 mM VP-CoA slightly inhibited MCAD alone. At 0.3 mM, it moderately inhibited SCAD, MCAD and IVD: the inhibition ranged from 18% for IVD to 25% for MCAD.
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Ito, M., Ikeda, Y., Finocchiaro, G. et al. THE ENZYMATIC BASIS FOR THE METABOLISM AND INHIBITORY ACTION OF VALPROATE (VP): DEHYDROGENATION OF VP-CoA BY 2-METHYL-BRANCHED CHAIN ACYL-CoA DEHYDROGENASE (2-me BCAD). Pediatr Res 21 (Suppl 4), 343 (1987). https://doi.org/10.1203/00006450-198704010-01053
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DOI: https://doi.org/10.1203/00006450-198704010-01053