Early Structural and Functional Changes in Liver of Rats Treated with a Single Dose of Valproic Acid

Jézéquel, A.M.; Bonazzi, Patrizia; Novelli, Giuseppe; Venturini, C.; Orlandi, F.

doi:10.1002/hep.1840040611

Cited by 43 publications

(16 citation statements)

References 17 publications

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“…In livers from vehicle-or VPA-treated wild-type mice or vehicle-treated jvs ϩ/Ϫ mice, almost no caspase-3-positive cells were detectable. Similar histological findings have been reported in another study exploring the hepatic effects of VPA (Jezequel et al, 1984).…”

Section: Table 1 Characterization Of the Animalssupporting

confidence: 90%

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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Section: Table 1 Characterization Of the Animalssupporting

confidence: 90%

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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“…This does not exclude that a reduction might occur at a later period. In rats VPA was capable of reducing hepatic glutathione for several hours [49]. In our studies, the level of plasma Fig.…”

Section: Suggested Explanation Of the Teratogenicity Of Vpa By The Alsupporting

confidence: 55%

VPA-induced neural tube defects in mice. I. altered metabolism of sulfur amino acids and glutathione

Hishida

Nau

1998

Teratog. Carcinog. Mutagen.

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“…In a previous study of VPA-induced choleresis, no gross structural alterations were reported at the level of the canalicular wall or at the level of the tight junctions, which could account for increased access of fluid into bile (13). This is further confirmed in the present study by the absence of changes in lanthanum penetration of the junctional complexes.…”

Section: Discussionsupporting

confidence: 89%

“…The increase in bile flow occurring after administration of VPA followed the pattern previously described (11)(12)(13). At 20 min, a twofold increase was evident.…”

Section: Bile Secretionsupporting

confidence: 80%

The fate of electron opaque tracers (horseradish peroxidase and lanthanum chloride) during valproic acid‐induced choleresis

Jézéquel

Macarri

Rinaldesi

et al. 1986

Liver

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ABSTRACT— Horseradish peroxidase (HRP) and lanthanum chloride (LaCl3) are useful tools for, respectively, the study of vesicular transport through the hepatocyte and the study of the permeability of junctional complexes. These tracers have been used to detect the changes associated with the choleresis independent of bile acids induced by valproic acid (VPA) in rats. The animals were given a single dose of VPA (600 mg/kg, ip). HRP (100 mg/kg) or 5 mM LaCl3 were given intraportally after 1 h, when bile flow had increased twofold. The excretion of HRP in bile was measured colorimetrically up to 2 h after HRP. Ultrastructural morphometry was conducted on liver of intact rats taken from 1 to 40 min after HRP. The volume density (VD) of HRP‐containing vesicles and of HRP‐containing multivesicular bodies (MVB) was counted. In VPA‐treated rats, HRP appeared in bile with a peak showing at 5 min against 20 min in controls, but the total amount of HRP excreted was less than in controls. The intrahepatocytic vesicular transport of HRP was also modified, showing a peak at 3 min in VPA‐treated rats compared to 10 min in controls, together with a decreased VD of pericanalicular vesicles. This was accompanied by an increase of HRP‐containing MVB, already evident at 5 min. VPA‐induced changes in HRP transport through the hepatocytes appeared twofold: 1) during VPA‐induced stimulation of bile flow, there was an early and short‐lived increase of transcellular transport and biliary elimination of HRP: 2) a diversion of HRP towards the indirect, lysosomal pathway apparently occurred, in agreement with previous findings concerning the formation of numerous cytolysomes induced by VPA (Hepatology 1984: 4: 1159–1166). The decreased amount of HRP excreted in bile could be accounted for by a diversion of HRP towards the degradation pathway. The pattern of distribution of LaCl3 was similar in VPA‐treated animals and in controls, suggesting that gross structural alterations of the junctional complexes are unlikely to occur during VPA‐induced choleresis.

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Early Structural and Functional Changes in Liver of Rats Treated with a Single Dose of Valproic Acid

Cited by 43 publications

References 17 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

VPA-induced neural tube defects in mice. I. altered metabolism of sulfur amino acids and glutathione

The fate of electron opaque tracers (horseradish peroxidase and lanthanum chloride) during valproic acid‐induced choleresis

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