Induction of liver metallothionein contribute to the developmental toxicity of valproic acid in rat

ABSTRACT

There is an increased risk of neural tube defects and axial skeletal malformations among infants born by mothers who had received valproic acid. The aim of the present study is, if administration of valproic acid can induce maternal hepatic Metallothionein [MT] synthesis and so secondary decrease of plasma Zn. In the present experimental study, mated rats were divided into four groups of 12 animals each [control, valproic acid [VPA], valproic acid + zinc [VPA+ Zn] and Zinc [Zn] groups. The VPA group received 300 mg/kg valproic acid; daily. The control group received an equal volume of 0.9% NaCI. The VPA+ Zn group received 300 mg/kg VPA as well as 30 mg/kg zinc sulfate, and the Zn group received 30 mg/kg zinc sulfate, daily. These drugs were administered intraperitoneally from day 6 through day 15 of gestation. Dams were killed on GD 16 or 20. Blood was drawn to determine plasma zinc; furthermore, maternal liver Zn and MT were also determined. The zinc concentration in the plasma of rats treated with valproic acid was significantly lower than those of the other groups on GD 16 [p=0.004], but liver Zn [p=0.016] and MT [p=0.004] were significantly higher than those of the control group. On GD 20 the incidence of skeletal malformations and neural tube defects tended to be higher in VPA group than VPA+ Zn treated group and no anomalies were seen in the control group. The results from the present experiment support hypothesis that one of biochemical lesions causing the teratogenicity of VPA is a drug -induced maternal plasma zinc deficiency secondary to Metallothionein induction in liver