In vivo effect of sodium valproate on mouse liver

Cell Mol Life Sci. 1999 Oct 15;56(3-4):363-9. doi: 10.1007/s000180050437.

Abstract

The in vivo effect of sodium valproate (SV) on the activity of uridine diphosphate glucuronosyltransferase (UDP-GT) and hepatotoxicity in the mouse liver was studied. Mice were injected intraperitoneally (IP) with SV at doses varying from 50 to 800 mg/kg per day, for six consecutive days (dose-response group) or at a standard dose of 300 mg/g per day for 2-10 days (time-response group), whereas the controls were injected with normal saline. Valproic acid levels had a positive correlation to the dose (P < 0.001) and duration of drug administration (P = 0.006). A gradual increase in UDP-GT activity was observed in doses of up to approximately 400 mg/kg per day, whereas in higher doses the enzyme activity gradually decreased. The time course of UDP-GT activity at the standard dose of 300 mg/kg per day increased progressively, with a maximum up to the sixth day and then had a gradual reduction. Hepatic necrosis (which was unrelated to the dose or the duration of drug administration) was found in 13% of the SV-treated animals and in none of the controls. We conclude that at an optimal dose (300-400 mg/kg per day) and at a time course of 6 days, SV causes liver UDP-GT induction, whereas in higher doses and longer duration of administration, UDP-GT activity is gradually reduced. SV also causes hepatotoxicity unrelated to dose and time course.

MeSH terms

  • Alanine Transaminase / blood
  • Alanine Transaminase / drug effects
  • Animals
  • Anticonvulsants / pharmacology*
  • Dose-Response Relationship, Drug
  • Female
  • Glucuronosyltransferase / drug effects
  • Glucuronosyltransferase / metabolism
  • Injections, Intraperitoneal
  • Liver / drug effects*
  • Liver / enzymology
  • Liver / pathology
  • Male
  • Mice
  • Time Factors
  • Valproic Acid / blood
  • Valproic Acid / pharmacology*

Substances

  • Anticonvulsants
  • Valproic Acid
  • Glucuronosyltransferase
  • Alanine Transaminase