Binding of a valproate metabolite to the trifunctional protein of fatty acid oxidation

Baldwin, Graham S.; Abbott, Frank S.; Nau, Heinz

doi:10.1016/0014-5793(96)00267-0

Cited by 24 publications

(16 citation statements)

References 11 publications

(17 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A reduced activity of complex IV associated with VPA treatment not only explains impaired oxidation of succinate and L-glutamate but also that of palmitate, as observed in this study (Table 3). On the other hand, the reduced activity of mitochondrial ␤-oxidation, which has been described in other studies assessing hepatic toxicity of VPA (Turnbull et al, 1983;Baldwin et al, 1996), can be explained most probably by interactions of toxic metabolites of VPA with enzymes involved in ␤-oxidation (Ito et al, 1990;Baldwin et al, 1996). A comparison of palmitate oxidation in vivo and in vitro reveals that in vivo, ␤-oxidation was only impaired in VPAtreated jvs ϩ/Ϫ mice, whereas in vitro, palmitate oxidation was also reduced in liver mitochondria from VPA-treated wild-type mice.…”

Section: Discussionmentioning

confidence: 97%

Toxicity of Valproic Acid in Mice with Decreased Plasma and Tissue Carnitine Stores

Knapp

Todesco²,

Beier³

et al. 2007

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The aim of this study was to investigate whether a decrease in carnitine body stores is a risk factor for valproic acid (VPA)-associated hepatotoxicity and to explore the effects of VPA on carnitine homeostasis in mice with decreased carnitine body stores. Therefore, heterozygous juvenile visceral steatosis (jvs) ϩ/Ϫ mice, an animal model with decreased carnitine stores caused by impaired renal reabsorption of carnitine, and the corresponding wild-type mice were treated with subtoxic oral doses of VPA (0.1 g/g b.wt./day) for 2 weeks. In jvs ϩ/Ϫ mice, but not in wild-type mice, treatment with VPA was associated with the increased plasma activity of aspartate aminotransferase and alkaline phosphatase. Furthermore, jvs ϩ/Ϫ mice revealed reduced palmitate metabolism assessed in vivo and microvesicular steatosis of the liver. The creatine kinase activity was not affected by treatment with VPA. In liver mitochondria isolated from mice that were treated with VPA, oxidative metabolism of L-glutamate, succinate, and palmitate, as well as ␤-oxidation of palmitate, were decreased compared to vehicle-treated wild-type mice or jvs ϩ/Ϫ mice. In comparison to vehicle-treated wild-type mice, vehicle-treated jvs ϩ/Ϫ mice had decreased carnitine plasma and tissue levels. Treatment with VPA was associated with an additional decrease in carnitine plasma (wildtype mice and jvs ϩ/Ϫ mice) and tissue levels (jvs ϩ/Ϫ mice) and a shift of the carnitine pools toward short-chain acylcarnitines. We conclude that jvs ϩ/Ϫ mice reveal a more accentuated hepatic toxicity by VPA than the corresponding wildtype mice. Therefore, decreased carnitine body stores can be regarded as a risk factor for hepatotoxicity associated with VPA.

show abstract

Section: Discussionmentioning

confidence: 97%

Toxicity of Valproic Acid in Mice with Decreased Plasma and Tissue Carnitine Stores

Knapp

Todesco²,

Beier³

et al. 2007

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…Complete resolution of the four VPA acyl-CoA intermediates was achieved with the HPLC system used. The mean (relative standard deviation, rsd %) of the retention times obtained in interday (n ϭ 7) experiments for the standards by order of elution were, respectively: 3-OH-valproyl-CoA, 11.77 min (12.0%); 3-keto-valproyl-CoA, 12.23 min (10.9%); ⌬ 2(E) -valproyl-CoA, 16.36 min (6.9 %); valproyl-CoA, 16.95 min (6.6 %).…”

Section: Quantification Of Intramitochondrial Levels Of Vpa-acyl-coa mentioning

confidence: 99%

“…Furthermore, the enzymatic basis for the inhibition of fatty acid oxidation by VPA has not been resolved unambiguously. It is important to stress that most of the reported in vitro studies have been performed with the drug and its metabolites in their free acid form (see, e.g., 16,17). Remarkably, very few studies have been performed with the actual CoA esters and, if done, these studies were mainly limited to valproyl-CoA (5,6,13).…”

mentioning

confidence: 99%

Synthesis and Intramitochondrial Levels of Valproyl-Coenzyme A Metabolites

Silva

Ruiter

IJlst

et al. 2001

Analytical Biochemistry

View full text Add to dashboard Cite

“…The S-CoA ester of 3-oxo-⌬ 2,4 -VPA (Fig. 22) has been proposed as an ultimate hepatotoxic species (Baillie, 1988;Baldwin et al, 1996), and both ⌬ 4 -VPA and ⌬ 2,4 -VPA are hepatotoxins in rats (Kesterson et al, 1984). An intramolecular deuterium isotope effect (ϳ6) has been observed on the cytochrome P450-mediated oxidation of VPA to ⌬ 4 -VPA using 4,4-2 H-VPA as a substrate ).…”

Section: Fig 21 Partial Scheme For the Metabolism Of Phenacetin Viamentioning

confidence: 99%

The Use of Deuterium Isotope Effects to Probe the Active Site Properties, Mechanism of Cytochrome P450-Catalyzed Reactions, and Mechanisms of Metabolically Dependent Toxicity

Nelson¹,

Trager²

2003

Drug Metab Dispos

142

121

View full text Add to dashboard Cite

This article is available online at http://dmd.aspetjournals.org ABSTRACT:Critical elements from studies that have led to our current understanding of the factors that cause the observed primary deuterium isotope effect, (k H /k D )obs, of most enzymatically mediated reactions to be much smaller than the "true" or intrinsic primary deuterium isotope effect, k H /k D , for the reaction are presented. This new understanding has provided a unique and powerful tool for probing the catalytic and active site properties of enzymes, particularly the cytochromes P450 (P450). Examples are presented that illustrate how the technique has been used to determine k H /k D , and properties such as the catalytic nature of the reactive oxenoid intermediate, prochiral selectivity, the chemical and enzymatic mechanisms of cytochrome P450-catalyzed reactions, and the relative active site size of different P450 isoforms. Examples are also presented of how deuterium isotope effects have been used to probe mechanisms of the formation of reactive metabolites that can cause toxic effects.Historically, the determination of deuterium isotope effects has been a powerful tool to help unravel the intricacies of carbon-hydrogen bond cleavage and define the mechanism of specific chemical reactions. The intrinsic primary isotope effect, k H /k D , for a reaction is the magnitude of the isotope effect on the rate constant for the bond-breaking step (C-H versus C-D) of the reaction and is related to the symmetry of the transition state for that step. The larger the isotope effect, the more symmetrical the transition state, with the theoretical limit being 9 at 37°C in the absence of tunneling effects (Bell, 1974). The chemical events leading to the transition state and subsequent formation of products are the descriptors of a chemical mechanism. It is the relationship of k H /k D to transition state that provides mechanistic insight. Thus, k H /k D is the quantity that needs to be known, and for homogenous chemical reactions, the experimentally observed deuterium isotope effect, (k H /k D )obs, where (k H /k D )obs is defined as the ratio of a kinetic parameter such as V max or V max /K m obtained from a nondeuterated substrate to a deuterated substrate, is identical to k H /k D . This is generally not true of enzymatically mediated reactions and is the reason for the much less successful application of deuterium isotope effects to such reactions until the system was better understood. The experimentally observed isotope effect, (k H /k D )obs, was invariably found to be much smaller than k H /k D , the intrinsic isotope effect for that reaction, thereby obscuring both meaning and mechanism. Even more perplexing was the observation that (k H /k D

show abstract

Binding of a valproate metabolite to the trifunctional protein of fatty acid oxidation

Cited by 24 publications

References 11 publications

Toxicity of Valproic Acid in Mice with Decreased Plasma and Tissue Carnitine Stores

Toxicity of Valproic Acid in Mice with Decreased Plasma and Tissue Carnitine Stores

Synthesis and Intramitochondrial Levels of Valproyl-Coenzyme A Metabolites

The Use of Deuterium Isotope Effects to Probe the Active Site Properties, Mechanism of Cytochrome P450-Catalyzed Reactions, and Mechanisms of Metabolically Dependent Toxicity

Contact Info

Product

Resources

About