Evidence for a Trigger Function of Valproic Acid in Xenobiotic‐Induced Hepatotoxicity

Abstract

The influence of the antiepileptic drug, valproic acid (2-n-propylpentanoic acid), on the hepatocellular capacity, to cope with an extrinsic oxidative stress was investigated. Freshly isolated rat hepatocytes exposed to therapeutic concentrations of valproic acid (0.25-1.0 mmol/l) were less resistant than controls, as evidenced by a significant cytotoxic response after challenge of the cells with a non-toxic dose of allyl alcohol (2-propen-1-ol). Valproic acid alone was not toxic to hepatocytes even at ten times higher concentrations (10 mmol/l), suggesting that cell damage was not a mere additive effect. Incubation with valproic acid plus allyl alcohol induced an irreversible depletion of hepatocellular glutathione, in contrast to allyl alcohol alone which induced a transient loss. Hepatocytes treated with valproic acid plus allyl alcohol were protected by N-acetylcysteine, a precursor of glutathione. These findings indicate that valproic acid affects hepatocellular defence mechanisms and suggest that a predisposition of hepatocytes to oxidative stress may play a role in the fatal hepatotoxicity of valproic acid in epileptic patients.

Apium graveolens modulates sodium valproate‐induced reproductive toxicity in rats

“…A growing body of evidence suggests increased levels of free radicals following treatment with VPA. A possible VPA biotransformation and/or alterations in natural antioxidants (Graf et al, '98;Klee et al, 2000;Bykov et al, 2004) may contribute to the VPA-associated complications. Antioxidants are, however, the primary candidates to counteract such toxic effect.…”

Irinotecan chemotherapy during valproic acid treatment: Pharmacokinetic interaction and hepatotoxicity

“…Valproic acid was shown to affect hepatocellular defense mechanisms against extrinsic oxidative stress and to produce oxidative stress itself. [55][56][57] In addition, it was suggested that a predisposition of hepatocytes to oxidative stress may play a role in the fatal hepatotoxicity of valproic acid. 55 Although its exact mechanism of action remains to be elucidated (that is, hepatic damage as a consequence of the higher exposure to 'free' SN-38 of valproic acid preexposed hepatocytes or the other way around), it seems that combining fully dosed irinotecan therapy with valproic acid may result in severe hepatotoxicity.…”

A Case Report on Lamotrigine and Sodium Valproate Induced Stevens-Johnson Syndrome

“…Sodium valproate chronic therapy or Sodium valproate overdose produces L-carnitine (LCAR) depletion and this could impair β-oxidation leading to increase in ω-oxidation pathway and further the formation of toxic metabolites leads to mucocutaneous reaction. Moreover, impairment of β-oxidation leads to hyper ammonemia which is the major cause of seizures; so, combination therapy with Lcarnitine is recommended [25][26][27] .…”