Pediatric Hepatic Drug Reactions

Roberts, Eve A.

doi:10.1007/978-3-642-61013-4_13

Cited by 2 publications

(1 citation statement)

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“…A common histologic finding in the hepatotoxicity of valproic acid is microvesicular steatosis which is indicative of impairment of mitochondrial ß-oxidation (Fromenty & Pessayre 1997). Clinical and pathological features prove liver failure to be an idiosyncratic reaction, and therefore valproic acid was designated a contingent hepatotoxin (Roberts 1996;Zimmerman & Ishak 1996). The present study is based on the assumption that valproic acid could have an impact on hepatocellular defence mechanisms, so that the liver can no longer cope adequately with the challenge of endogenous or exogenous stress.…”

Section: Discussionmentioning

confidence: 99%

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

Klee¹,

Johanssen

Ungemach

2000

Pharmacology & Toxicology

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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.

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Section: Discussionmentioning

confidence: 99%