Valproic acid derivatives signal for apoptosis and repair in vitro

Manuela G. Neuman*, Radu M. Nanau, Tawfeeq Shekh-Ahmad, Boris Yagen, Meir Bialer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Purpose: To determine the cytotoxicity of valproic acid (VPA) and its derivatives in human hepatoblastoma (HepG2) cells, and to study the possible toxicity of these compounds in human lymphocytes from patients with known hypersensitivity syndrome reactions (HSRs) to other medication. Methods: Cells were exposed to physiological doses of VPA, valnoctamide (VCD) and its one carbon homologue sec-Butyl-propyl-acetamide (SPD) for 2. h and for 24. h. Cell viability was measured using succinate dehydrogenase activity for hepatocytes and lymphocyte toxicity assay (LTA) for lymphocytes. Cytokines and apoptosis [cytokeratine 18 (cCK18-M30)] markers were quantitated by ELISA. Results: VCD and SPD presented lower cytotoxicity compared to VPA in cultured HepG2 cells. SPD led to cytotoxicity in lymphocytes. VPA and its derivatives increased the release of interferon (IFN)-γ and tumor necrosis factor (TNF)-α in media, but had no influence on the release of either interleukin (IL)-1 or IL-6. Significant increases in the release of IFN-γ and TNF-α were observed in lymphocytes exposed to high doses of VPA, and this increased further with exposure time. Significance: HepG2 cells exposed to VCD and SPD experienced lower direct cytotoxicity than those treated with VPA. Lymphocytes from patients that experienced HSR to other medication have shown cytotoxicity to VPA and its VPA derivatives-induced. High levels of pro-inflammatory cytokines were released in the cell culture media, suggesting that inflammation plays a key role in VPA-derivatives induced lymphocyte toxicity.

Original languageAmerican English
Pages (from-to)1532-1537
Number of pages6
JournalClinical Biochemistry
Issue number15
StatePublished - Oct 2013

Bibliographical note

Funding Information:
The work was funded by In Vitro Drug Safety and Biotechnology .


  • Apoptosis
  • Drug-induced liver damage
  • HepG2
  • Hypersensitivity syndrome
  • Mitochondria
  • Valproic acid derivatives


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