Valproate is teratogenic due to neural tube defects. Its mechanism of teratogenicity involves:

• A Direct inhibition of DNA polymerase in rapidly dividing neuroepithelial cells
• B Activation of retinoic acid receptors causing aberrant Hox gene expression
• C Folate receptor downregulation in placental trophoblasts blocking maternal folate transfer
• D Inhibition of histone deacetylase (HDAC) and folate metabolism, altering gene expression during early neural tube closure ✓

Explanation

Valproate inhibits HDAC enzymes, causing histone hyperacetylation and dysregulation of developmental gene expression, particularly genes controlled by retinoic acid signalling and Wnt pathways involved in neural tube closure. Additionally, valproate impairs folate metabolism (by interfering with folate-dependent one-carbon reactions), and folate is essential for neural tube closure by day 26 post-conception. High-dose folate supplementation (5 mg/day) is recommended but does not completely eliminate the risk.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.