Inhibition of medium-chain fatty acid β-oxidationinvitro by valproic acid and its unsaturated metabolite, 2-n-propyl-4-pentenoic acid

Bjorge, S. M.; Baillie, Thomas A.

doi:10.1016/0006-291x(85)91014-9

Cited by 82 publications

(24 citation statements)

References 26 publications

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“…2). When the properties of A4-VPA were examined in vitro, it was found that the compound was an effective inhibitor of the ~-oxidation of mediumchain fatty acids in rat liver homogenates [11] and that it was cytotoxic to rat hepatocytes in culture [31]. Moreover, it was shown that radiolabelled A4-VPA became bound covalently to rat liver proteins both in vitro and in vivo, and that this binding was decreased by 4-pentenoic acid, an inhibitor of fatty acid ~-oxidation [32].…”

Section: 'A 4 Pathway' Of Valproate Metabolismmentioning

confidence: 99%

“…Interestingly, a common histological feature in VPA-induced liver damage has been reported to be microvesicular steatosis (again indicative of impaired ~-oxidation), in which hepatocytes are infiltrated by lipid droplets and mitochondria are swollen or ruptured [3 8]. In studies with rats, high doses of VPA have been shown to induce hepatic steatosis [9 10] and to inhibit the ~-oxidation of medium-chain fatty acids in liver homogenates [11]. Collectively, these findings indicate that the mitochondrial fatty acid B-oxidation complex is severely compromised in VPAassociated hepatotoxicity, and suggest that an understanding of the interaction of VPA with this important enzyme system may provide some clues as to the biochemical mechanism(s) of the organ damage caused by this drug.…”

Section: Introductionmentioning

confidence: 99%

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Metabolism of valproate to hepatotoxic intermediates

Baillie

1992

Pharmaceutisch Weekblad Scientific Edition

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A number of lines of evidence indicate that metabolites of valproate rather than the parent drug, mediate the microvesicular steatosis which characterizes valproate-associated liver injury. In this article, two mechanisms are discussed whereby valproate may cause hepatic steatosis through interference with the process of fatty acid beta-oxidation. In the first, valproate itself enters the mitochondrion where it completes for the enzymes and/or co-factors involved in the beta-oxidation of endogenous substrates, while in the second, valproate is metabolized via the hepatotoxic terminal olefin, delta 4-valproate, to a variety of chemically reactive intermediates which inhibit key enzymes in the beta-oxidation cycle.

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Section: 'A 4 Pathway' Of Valproate Metabolismmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metabolism of valproate to hepatotoxic intermediates

Baillie

1992

Pharmaceutisch Weekblad Scientific Edition

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“…Numerous studies have shown that livers from rats treated with VPA show microvesicular steatosis [14][15][16]. VPA has been shown to inhibit fatty acid/~-oxidation in rats and humans [17][18][19][20]. Becker and Harris [17] proposed that either the co-enzyme A (CoA) thioester of VPA (VPA-CoA) itself or the sequestration of CoA cause inhibition of hepatic metabolic processes.…”

Section: Metabolic Effects Of Valproatementioning

confidence: 99%

“…It has been suggested that A4-VPA and other possible metabolites of VPA cause the idiosyncratic hepatotoxicity [43]. Indeed, A4-VPA has been shown to inhibit/~-oxidation in vitro [18] and is more effective than VPA in producing liver steatosis in rats [15 44]. Also, the formation clearance of A4-VPA was increased twofold in patients treated with both carbamazepine plus VPA and phenytoin plus VPA [45].…”

Section: Toxic Metabolitesmentioning

confidence: 99%

Valproate hepatotoxicity syndrome: Hypotheses of pathogenesis

Stephens

1992

Pharmaceutisch Weekblad Scientific Edition

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Therapeutic use of the anticonvulsant valproate (VPA) has been associated with a rare, but severe and often fatal hepatotoxicity. Cases usually present with lethargy, anorexia, and vomiting with rapid progression to coma. Liver histopathology is characterized by steatosis with and without necrosis. In some instances only necrosis was present. Several hypotheses of pathogenesis have been postulated. These deal mainly with biochemical systems that are known to be affected by VPA, or with the possible idiosyncratic production of toxic VPA metabolites, especially delta 4-VPA. At present, no hypothesis entirely explains the diverse characteristics of the disorder.

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“…These findings provide the first evidence that cytochrome P-450 mediated 4,5-desaturation of VPA discriminates between the two prochiral propyl groups of this drug and also support the results of previous experiments with subcellular preparations which indicated that pretreatment of rats with phenobarbital induces biotransformation of VPA to the hepatotoxic terminal olefin A4-VP A. Introduction 2-n-Propyl-4-pentenoic acid (A4-VPA;' 1, Figure l), a hepatotoxic olefinic metabolite of the antiepileptic drug valproic acid (VPA; 2, Figure l), has been shown to act as an inhibitor of both cytochrome P-450 and @-oxidation enzymes in rat liver (1,2). The mechanisms underlying these inhibitory actions are believed to involve, in both cases, enzyme-catalyzed activation of A4-VPA to reactive, electrophilic intermediates which bind covalently to, and thereby destroy, their respective target enzymes.…”

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confidence: 99%

Enantiotopic differentiation during the biotransformation of valproic acid to the hepatotoxic olefin 2-n-propyl-4-pentenoic acid

Porubek¹,

Barnes²,

Meier³

et al. 1989

Chem. Res. Toxicol.

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The enantiomers of 2-[( 3-13C]-n-propyl)pentanoic acid [(R)- and (S)-[13C]VPA] were employed as metabolic probes to investigate stereochemical aspects of the biotransformation of valproic acid (VPA) to 2-n-propyl-4-pentenoic acid (delta 4-VPA), a hepatotoxic metabolite of VPA. When incubated with hepatocytes freshly isolated from untreated male rats, each labeled substrate (initial concentration 1.0 mM) underwent metabolism to [13C]-delta 4-VPA, the formation of which was time-dependent and occurred at a rate of ca. 20 ng/(10(6) cells.4-h incubation). Analysis of this unsaturated metabolite by GC-MS techniques revealed that, following incubation of (R)-[13C]VPA, desaturation had taken place preferentially (by a factor of approximately 4) on the labeled propyl group (i.e., on the R side chain). Parallel incubations with (S)-[13C]VPA supported this conclusion, in that metabolism of this isotopic variant of VPA led to a terminal olefin that also was predominantly (83 +/- 2%) of R configuration (in this case oxidized selectively on the unlabeled side chain). Hence, biotransformation of VPA to delta 4-VPA in rat hepatocytes occurs with marked enantiotopic differentiation, favoring production of the R enantiomer of this chiral metabolite. When rats were pretreated with phenobarbital (80 mg kg-1 day-1 ip for 3 days) prior to isolation of hepatocytes, the overall rate of metabolism of VPA to delta 4-VPA over the 4-h incubation period increased approximately 3-fold, while the degree of product enantioselectivity was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

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Inhibition of medium-chain fatty acid β-oxidationinvitro by valproic acid and its unsaturated metabolite, 2-n-propyl-4-pentenoic acid

Cited by 82 publications

References 26 publications

Metabolism of valproate to hepatotoxic intermediates

Metabolism of valproate to hepatotoxic intermediates

Valproate hepatotoxicity syndrome: Hypotheses of pathogenesis

Enantiotopic differentiation during the biotransformation of valproic acid to the hepatotoxic olefin 2-n-propyl-4-pentenoic acid

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