In vitro effects of valproate and valproate metabolites on mitochondrial oxidations

Ponchaut, Sylvie; Hoof, F. Van; Veitch, Keith

doi:10.1016/0006-2952(92)90324-c

Cited by 99 publications

(58 citation statements)

References 31 publications

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“…Mechanisms of toxicity rely on mitochondrial b oxidation inhibition followed by the appearance of microvesicular steatosis [80] . Mitochondrial dysfunction follows the microsomal production of toxic metabolites (4-ene-valproate, 2,4-diene-valproate) [81] , decreased activity of complex Ⅳ of the respiratory chain, and depletion of coenzyme A (CoA) and carnitine [80] . Preexisting mitochondrial impairment or deficiency of cofactors involved with valproate metabolism (e.g.…”

Section: Direct Toxicitymentioning

confidence: 99%

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

Grattagliano

Bonfrate

Diogo

et al. 2009

WJG

123

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Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local O 2 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca 2+ -dependent ATPase, reduced capability to sequester Ca 2+ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.

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Section: Direct Toxicitymentioning

confidence: 99%

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

Grattagliano

Bonfrate

Diogo

et al. 2009

WJG

123

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“…Glucuronidation and β-oxidation are quantitatively the most important routes of biotransformation, generating a complex pattern of intermediates (Baillie 1992) which could potentially interfere with mitochondrial metabolism at different levels. In the past, several papers have described inhibitory effects of VPA and its metabolites on mitochondrial oxidative phosphorylation, both in vitro (Haas et al 1981;Becker and Harris 1983;Ponchaut et al 1992) and in vivo (Rumbach et al 1983). However, the results are not easily comparable and the reported data are quite contradictory.…”

Section: Short Communicationmentioning

confidence: 99%

Valproate inhibits the mitochondrial pyruvate‐driven oxidative phosphorylation in vitro

Silva

Ruiter

IJlst

et al. 1997

J of Inher Metab Disea

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“…Because VPA has been shown to impair mitochondrial ␤-oxidation (Levy et al, 1990;Ponchaut et al, 1992b;Fromenty and Pessayre, 1995) and considering our results that were obtained in vivo (see Table 2), we investigated the effect of VPA on the metabolism of palmitate by isolated liver mitochondria. VPA treatment significantly decreased palmitate oxidation by 44% in wild-type and by 35% in jvs ϩ/Ϫ mice compared with their vehicle-treated controls.…”

Section: Table 1 Characterization Of the Animalsmentioning

confidence: 99%

“…Microvesicular steatosis of the liver, one of the most important histological findings in VPA-induced liver failure (Zafrani and Berthelot, 1982;Zimmerman and Ishak, 1982;Dreifuss et al, 1987;Krähenbü hl et al, 1995), may be caused by impaired hepatic ␤-oxidation (Fromenty and Pessayre, 1995;Spaniol et al, 2001b). Different mechanisms have been proposed to explain inhibition of mitochondrial ␤-oxidation by VPA, among them microsomal production of toxic metabolites, e.g., 4-ene-VPA and 2,4-diene-VPA (Gram and Bentsen, 1985;Tennison et al, 1988;Ponchaut et al, 1992b;Ishikura et al, 1996), decreased activity of complex IV of the respiratory chain, and/or depletion of the hepatic pools of CoASH and/or carnitine (Ponchaut and Veitch, 1993;Krähenbü hl et al, 1995). Pre-existing mitochondrial diseases, e.g., impaired ␤-oxidation or impaired function of the respiratory chain, have been proposed to represent risk factors for VPA-associated mitochondrial dysfunction and therefore for liver failure (Chabrol et al, 1994;Lam et al, 1997;Krähenbü hl et al, 2000).…”

mentioning

confidence: 99%

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

Knapp

Todesco²,

Beier³

et al. 2007

J Pharmacol Exp Ther

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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.

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In vitro effects of valproate and valproate metabolites on mitochondrial oxidations

Cited by 99 publications

References 31 publications

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

Valproate inhibits the mitochondrial pyruvate‐driven oxidative phosphorylation in vitro

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

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