Acta Medica Iranica 2004. 42(1):10-15.

"ALTERED PLASMA ZINC LEVEL CONTRIBUTES TO THE DEVELOPMENTAL TOXICITY OF VALPROIC ACID IN SKELETAL SYSTEM OF RAT"
M.Akbari1, F. Abolhassani, M. Azizi, A.R. Dehpour, M.Ansari, M.A. Ahmadi Faghih A. Hedayatpour

Abstract


Valproic acid is one of the main antiepileptic drugs. There is an increased risk of neural tube
defects and axial skeletal malformations among infants born to women who had received valproic acid.
There is a hypothesis that one biochemical abnormality underlying the teratogenicity of valproic acid is a
drug-induced reduction in maternal plasma zinc .In the present experimental study mated rats were
divided into four groups of 8 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% NaCl. The VPA+ Zn group received 300 mg/kg VPA and 30 mg/kg
zinc sulfate and the Zn group received 30 mg/kg zinc sulfate, daily. Valproic acid, NaCl, and Zn were
administered intraperitonealy from day 6 through day 15 of gestation. On day 16, six rats of each group
were authanized and the other rats were scarified on gestational day (GD) 20 to evaluate the skeletal
system among the elder fetuses. Blood was drawn to determine plasma zinc. The data were analyzed by
using analysis of variance (Kruskal -Wallis test). The zinc concentration in the plasma of rats treated with
valproic acid was significantly lower than those of the other groups on 16 GD (P=0.004). Some
anomalies such as hydrocephaly, spina bifida, hemivertebrate, and rib malformations were seen in VPA
treated group. Low percentage of rib anomalies and spina bifida were observed in the VPA+ Zn treated
group while no skeletal anomalies were seen in Zn and control groups. The results from the present
experiment support the hypothesis that one of the biochemical abnormalities causing the teratogenicity of
VPA is a drug–induced maternal plasma zinc deficiency, and possibly, it may also result in reduction of
embryonic Zn.

Keywords


Teratogenicity, valproic acid, zinc, skeletal malformation,

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