Acute Hepatic Failure Associated with the Use of Sodium Valproate

Suchy, Frederick J.; Balistreri, William F.; Buchino, John J.; Sondheimer, Judith M.; Bates, Stephen; Kearns, Gregory L.; Stull, John D.; Bove, Kevin E.

doi:10.1056/nejm197904263001706

Cited by 150 publications

(48 citation statements)

References 18 publications

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“…Exposure to valproate can protect HepG2 cells from ER stress-induced apoptosis The use of valproate as an anti-convulsant or anti-epileptic drug has been associated with hepatotoxicity in humans (Suchy et al, 1979). The mood-stabilizing effects of valproate occur at plasma concentrations over 0.35 mM and toxicity is observed at concentrations over 1.4 mM (Bowden et al, 1994;McElroy and Keck, 1995).…”

Section: Resultsmentioning

confidence: 99%

Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3

Kim

Shi²,

Austin

et al. 2005

Journal of Cell Science

220

193

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A wide range of agents and conditions are known to disrupt the ability of the endoplasmic reticulum (ER) to fold proteins properly, resulting in the onset of ER dysfunction/stress. We and others have shown that ER stress can induce intracellular lipid accumulation through the activation of the sterol responsive element binding proteins (SREBPs) and initiate programmed cell death by activation of caspases. It has been suggested that ER stress-induced lipid accumulation and cell death play a role in the pathogenesis of disorders including Alzheimer's disease, Parkinson's disease, type-1 diabetes mellitus and hepatic steatosis. Here we show that exposure of HepG2 cells to the branch chain fatty acid, valproate, increases cellular resistance to ER stress-induced dysfunction. Two distinctly different potential mechanisms for this protective effect were investigated. We show that exposure to valproate increases the expression of chaperones that assist in the folding of proteins in the ER including GRP78/BiP, GRP94, PDI and calreticulin as well as the cytosolic chaperone, HSP70. However, exposure of HepG2 cells to valproate does not decrease the apparent ER stress response in cells challenged with tunicamycin, A23187 or glucosamine, suggesting that valproate-conferred protection occurs downstream of ER dysfunction. Finally, we demonstrate that valproate directly inhibits the glycogen synthase kinases (GSK)-3α/β. The ability of lithium, another inhibitor of GSK3α/β to protect cells from ER stress-induced lipid accumulation suggests that GSK3 plays a central role in signaling downstream effects of ER stress. Strategies to protect cells from agents/conditions that induce ER stress may have potential in the treatment of the growing number of diseases and disorders linked to ER dysfunction.

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Section: Resultsmentioning

confidence: 99%

Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3

Kim

Shi²,

Austin

et al. 2005

Journal of Cell Science

220

193

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“…In 12-and 24-hr samples, all parenchymal cells exhibited normal features. 3. Part of three hepatocytes 5 hr after administration of NaVPA (600 mg per kg).…”

Section: Electron Microscopymentioning

confidence: 99%

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

et al. 1984

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Valproic acid (VPA) is a simple fatty acid largely used as anticonvulsivant agent. Side effects are uncommon, but cases of fatal hepatic failure have been reported. To elucidate the mechanism of VPA-induced hepatotoxicity, the functional and structural changes associated with administration of sodium valproate (NaVPA) to rats (200 or 600 mg per kg, i.p.) were analyzed. NaVPA produced an immediate, dose-dependent and prolonged increase in bile salt-independent bile flow with a decrease in biliary cholesterol and phospholipid output. At 3 and 5 hr, marked ultrastructural changes were evident in hepatocytes, including formation of autophagic vacuoles engulfing altered mitochondria and occasionally peroxisomes. A modest accumulation of lipoprotein particles was evident at 5 hr in the Golgi cisternae. Twelve-hour samples appeared normal. Bile canaliculi and junctional complexes remained unaltered throughout. The changes observed differ from those previously reported with other hydrocholeretics, such as diethylmaleate; they are likely related to hepatic biotransformation of VPA, which undergoes beta and omega-oxidation, and glucuronidation. While VPA-induced choleresis reflects the physiological osmotic effect of the glucuronide excreted in bile, the ultrastructural changes likely reflect interference by VPA with beta-oxidation of endogenous fatty acids and temporary accumulation of transformation products in the mitochondrial matrix.

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“…Biochemically, a number of abnormalities have been documented, i.e. inhibition of oxidative phosphorylation in isolated rat liver mitochondria [6], depletion of liver glycogen stores [7,8], fatty degenera tion of the liver [8,9], inhibition of lactate Liver weight, g/100 g body weight 118 ± 4.8 (21) Protein, mg/g liver 91.6 ± 5.1 (12) Results are mean values ± SEM with the number of animals in parentheses.…”

Section: Introductionmentioning

confidence: 99%

Effect of Sodium Valproate on Subcellular Fraction Enzymes in Rat Liver

Cotariu¹,

Evans²,

Zaidman³

1985

Enzyme

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Previous observations that valproic acid (VPA) causes hepatic damage prompted us to investigate the effect of large doses of the drug (0.6, 1.2 and 1.8 mmol/kg/day) on a number of liver enzymes located on different subcellular fractions. In mitochondria, glutamate dehydrogenase, aspartate aminotransferase and ornithine carbamyltransferase were significantly increased (1.8 mmol/kg/day). In microsomes, gamma-glutamyltransferase activity increased significantly (1.8 mmol/kg) and cytochrome P-450 content decreased significantly (1.2 and 1.8 mmol/kg). In cytosol, both aspartate and alanine aminotransferase activities were increased at all dose levels. These results indicate that VPA induces dose-dependent changes in some liver enzyme activities.

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Acute Hepatic Failure Associated with the Use of Sodium Valproate

Cited by 150 publications

References 18 publications

Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3

Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3

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

Effect of Sodium Valproate on Subcellular Fraction Enzymes in Rat Liver

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