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

Authors

  • Anne Marie Jezequel,

    Corresponding author
    1. Departments of Gastroenterology and Cell Pathology, University of Ancona, School of Medicine and Department of Gastroenterology, General Hospital “Umberto I”, Ancona, Italy
    • Anne Marie Jezequel, M.D., University of Ancona, CP 538, 60100 Ancona, Italy.
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  • Patrizia Bonazzi,

    1. Departments of Gastroenterology and Cell Pathology, University of Ancona, School of Medicine and Department of Gastroenterology, General Hospital “Umberto I”, Ancona, Italy
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  • Giuseppe Novelli,

    1. Departments of Gastroenterology and Cell Pathology, University of Ancona, School of Medicine and Department of Gastroenterology, General Hospital “Umberto I”, Ancona, Italy
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  • Cinzia Venturini,

    1. Departments of Gastroenterology and Cell Pathology, University of Ancona, School of Medicine and Department of Gastroenterology, General Hospital “Umberto I”, Ancona, Italy
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  • Francesco Orlandi

    1. Departments of Gastroenterology and Cell Pathology, University of Ancona, School of Medicine and Department of Gastroenterology, General Hospital “Umberto I”, Ancona, Italy
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Abstract

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 ultrastruc-tural 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 β and ω-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 β-oxidation of endogenous fatty acids and temporary accumulation of transformation products in the mitochondrial matrix.

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