The enzymatic basis for the metabolism and inhibitory effects of valproic acid: dehydrogenation of valproyl-CoA by 2-methyl-branched-chain acyl-CoA dehydrogenase

M, Ito; Ikeda, Yasuyuki; Arnez, John G.; Finocchiaro, Gaetano; Tanaka, Kay

doi:10.1016/0304-4165(90)90079-c

Cited by 66 publications

(43 citation statements)

References 26 publications

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“…This discrepancy with the literature may be related to methodologic differences or individual variations in the acylcarnitine excretion pattern of valproic acid-treated patients. Our findings suggest that valproic acid treatment may result in an inhibition of fatty acid oxidation partly at the level of MCAD and are in agreement with the recent finding of a moderate inhibitory effect of valproyl-CoA on human liver MCAD in vitro (29). However, they do not support the concept that conjugation of valproic acid with carnitine is an important "detoxifying" mechanism in the human.…”

Section: Discussionsupporting

confidence: 58%

Urinary Medium-Chain Acylcarnitines in Medium-Chain Acyl-CoA Dehydrogenase Deficiency, Medium-Chain Triglyceride Feeding and Valproic Acid Therapy: Sensitivity and Specificity of the Radioisotopic Exchange/High Performance Liquid Chromatography Method

et al. 1992

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ABSTRACT. To determine the sensitivity and specificity of detecting urinary medium-chain acylcarnitines for the diagnosis of MCAD deficiency, 114 urine specimens from 75 children with metabolic diseases and controls were analyzed in a blinded fashion using a radioisotopic exchange/HPLC method. All 47 patients with MCAD deficiency were correctly diagnosed using the criterion hexanoylcarnitine or octanoylcarnitine peak areas larger than those of other medium-chain acylcarnitines. The majority of them were tested during the asymptomatic state without L-carnitine loading. Four patients with other defects of fatty acid oxidation and three patients receiving valproic acid had a similar acvlcarnitine excretion uattern. To further examine the specificity of the method, eight infants receiving a diet enriched with medium-chain triglycerides and 13 additional patients receiving valproic acid were studied. Most of these also tested positive for MCAD deficiency by the above criterion. Analysis by a new gas chromatographic-mass spectrometric procedure revealed that octanoylcarnitine, not valproylcarnitine, was the most abundant medium-chain carnitine ester excreted by a patient treated with valproic acid. Quantitation of urinary hexanoylcarnitine and octanoylcarnitine showed considerable overlap among patients with MCAD deficiency and those receiving valproic acid or a medium-chain triglyceride-enriched diet. MCAD deficiency can be reliably detected in urine specimens by this method without the need for prior carnitine loading. However, other defects in fatty acid oxidation must be differentiated from MCAD deficiency, and a history of medium-chain triglyceride or valproic acid administration must be considered if the diagnosis of MCAD deficiency is sought through analysis of urinary acylcarnitines. (Pediatr Res 31: 545-551, 1992) Abbreviations MCAD, medium-chain acyl-CoA dehydrogenase C6, hexanoylcarnitine C8, octanoylcarnitine MCT, medium-chain triglyceride GC/MS, gas chromatography/mass spectrometry FAB/MS, fast atom bombardment/mass spectrometry MC, medium-chain acylcarnitine r.t., retention time DC, decanoylcarnitine MCAD deficiency is the most common inborn error of fatty acid oxidation (for review see Ref. I). It usually presents during the first 2 y of life as an acute episode of lethargy, coma, or unexpected death after a period of fasting, often associated with infection. Typical laboratory findings include hypoketotic hypoglycemia and dicarboxylic aciduria. A fatty liver is found on biopsy or at autopsy. The disease is characterized by sudden, lifethreatening metabolic crises carrying a high mortality rate, but the prognosis is excellent if such crises are successfully overcome or prevented by avoidance of fasting. Therefore, early diagnosis before a life-threatening event occurs is warranted.However, the diagnosis may be missed by routine GC/MS of urinary organic acids in the asymptomatic state unless a potentially dangerous fasting test is performed (1). Besides enzymatic (2, 3) and molecular (4) analysis, two...

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Section: Discussionsupporting

confidence: 58%

Urinary Medium-Chain Acylcarnitines in Medium-Chain Acyl-CoA Dehydrogenase Deficiency, Medium-Chain Triglyceride Feeding and Valproic Acid Therapy: Sensitivity and Specificity of the Radioisotopic Exchange/High Performance Liquid Chromatography Method

et al. 1992

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“…Previous work from Li et al (1991), Ito et al (1990), and our group (Silva et al, 2001b(Silva et al, , 2002(Silva et al, , 2004) has led to the partial resolution of the mitochondrial ␤-oxidation pathway of VPA. We concluded that the enzymes involved in the oxidation of straight-chain fatty acids, including very long-, long-, medium-, and short-chain acyl-CoA dehydrogenases, are not involved in the first dehydrogenation reaction of VPA.…”

Section: Introductionmentioning

confidence: 85%

Role of Isovaleryl-CoA Dehydrogenase and Short Branched-Chain Acyl-CoA Dehydrogenase in the Metabolism of Valproic Acid: Implications for the Branched-Chain Amino Acid Oxidation Pathway

Luis¹,

Ruiter²,

IJlst³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Many biological systems including the oxidative catabolic pathway for branched-chain amino acids (BCAAs) are affected in vivo by valproate therapy. In this study, we investigated the potential effect of valproic acid (VPA) and some of its metabolites on the metabolism of BCAAs. In vitro studies were performed using isovalerylCoA dehydrogenase (IVD), isobutyryl-CoA dehydrogenase (IBD), and short branched-chain acyl-CoA dehydrogenase (SBCAD), enzymes involved in the degradation pathway of leucine, valine, and isoleucine. The enzymatic activities of the three purified human enzymes were measured using optimized high-performance liquid chromatography procedures, and the respective kinetic parameters were determined in the absence and presence of VPA and the corresponding CoA and dephosphoCoA conjugates. Valproyl-CoA and valproyl-dephosphoCoA inhibited IVD activity significantly by a purely competitive mechanism with K i values of 74 ؎ 4 and 170 ؎ 12 M, respectively. IBD activity was not affected by any of the tested VPA esters. However, valproyl-CoA did inhibit SBCAD activity by a purely competitive mechanism with a K i of 249 ؎ 29 M. In addition, valproyl-dephosphoCoA inhibited SBCAD activity via a distinct mechanism (K i ‫؍‬ 511 ؎ 96 M) that appeared to be of the mixed type. Furthermore, we show that both SBCAD and IVD are active, using valproyl-CoA as a substrate. The catalytic efficiency of SBCAD turned out to be much higher than that of IVD, demonstrating that SBCAD is the most probable candidate for the first dehydrogenation step of VPA ␤-oxidation. Our data explain some of the effects of valproate on the branched-chain amino acid metabolism and shed new light on the biotransformation pathway of valproate.

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“…In addition, these acyl-CoA oxidations occur in one compartment: isovaleryl-CoA and 2-methylbutyryl-CoA are not oxidized by peroxisomes [25], whereas bile acyl-CoA is not significantly oxidizable by mitochondria [6,26]. The mitochondrial oxidation of valproyl-CoA has been documented elsewhere [ 13,141. The pathway is initiated by mitochondrial branchedchain acyl-CoA dehydrogenase and proceeds up to /3-ketoacyl-CoA formation but not further [13,14]. In peroxisomes, the situation appears to be distinct, and/?-oxidation concerns the acyl-CoA oxidase step, mainly.…”

Section: Discussionmentioning

confidence: 99%

CoA esters of valproic acid and related metabolites are oxidized in peroxisomes through a pathway distinct from peroxisomal fatty and bile acyl‐CoA β‐oxidation

et al. 1993

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In rat liver homogenates fortified with the appropriate cofactors (ATP and CoA), valproic acid induced H,02 production rates by far lower than those recorded on the straight medium-chain fatty acid n-octanoic acid. Using directly the CoA esters of these carboxylic acids as substrates for the rat liver H,O,-generating enzyme activities, valproyl-CoA, and n-octanoyl-CoA were found to induce similar oxidation rates. In the rat liver homogenates, cyanide-insensitive valproyl-CoA and octanoyl-CoA oxidations occurred at rates similar to those of valproyl-CoA and octanoyl-CoA oxidase(s), respectively. Studies on fractions obtained from rat liver postnuclear supernatants by isopycnic centrifugation on a linear sucrose density gradient disclose that the density distribution of valproyl-CoA oxidase superimposes to those of catalase, fatty acyl-CoA oxidase and cyanideinsensitive fatty acyl-CoA oxidation, three peroxisomal marker activities. By contrast, the cyanide-insensitive valproyl-CoA oxidation does not adopt the typical peroxisomal distribution of these activities but rather exhibits a mitochondrial localization with, however, a minor peroxisomal component. Interestingly enough, the comparative study of rat tissue distribution, inducibility by clofibrate and sensitivity to deoxycholate indicated that valproyl-CoA oxidase is an enzyme distinct from fatty acyl-CoA oxidase and bile acyl-CoA oxidase. Taken as a whole, the results presented here support the occurrence of a peroxisomal oxidation of the CoA ester of valproic acid and its d4-enoic derivate which might be characterized by two major features: initiation by an acyl-CoA oxidase distinct from fatty and bile acyl-CoA oxidases, and inability to complete thej3-oxidation cycle which would not proceed, at significant rates, further than the /I-hydroxyacyl-CoA dehydrogenation step in peroxisomes.

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The enzymatic basis for the metabolism and inhibitory effects of valproic acid: dehydrogenation of valproyl-CoA by 2-methyl-branched-chain acyl-CoA dehydrogenase

Cited by 66 publications

References 26 publications

Urinary Medium-Chain Acylcarnitines in Medium-Chain Acyl-CoA Dehydrogenase Deficiency, Medium-Chain Triglyceride Feeding and Valproic Acid Therapy: Sensitivity and Specificity of the Radioisotopic Exchange/High Performance Liquid Chromatography Method

Urinary Medium-Chain Acylcarnitines in Medium-Chain Acyl-CoA Dehydrogenase Deficiency, Medium-Chain Triglyceride Feeding and Valproic Acid Therapy: Sensitivity and Specificity of the Radioisotopic Exchange/High Performance Liquid Chromatography Method

Role of Isovaleryl-CoA Dehydrogenase and Short Branched-Chain Acyl-CoA Dehydrogenase in the Metabolism of Valproic Acid: Implications for the Branched-Chain Amino Acid Oxidation Pathway

CoA esters of valproic acid and related metabolites are oxidized in peroxisomes through a pathway distinct from peroxisomal fatty and bile acyl‐CoA β‐oxidation

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