title: Valproic acid derivatives signal for apoptosis and repair in vitro.
abstract: OBJECTIVE
  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 2h and for 24h. 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: In Vitro Drug Safety & Biotechnology, Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address: manuela.neuman@utoronto.ca.
authors.forename: Manuela G
authors.initials: MG
authors.lastname: Neuman
authors.forename: Radu M
authors.initials: RM
authors.lastname: Nanau
authors.forename: Tawfeeq
authors.initials: T
authors.lastname: Shekh-Ahmad
authors.forename: Boris
authors.initials: B
authors.lastname: Yagen
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
mesh_terms: D000577:Amides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004260:DNA Repair / Q000187:drug effects*; D063926:Drug Hypersensitivity Syndrome / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D007375:Interleukin-1 / Q000096:biosynthesis / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D053538:Keratin-18 / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000577:Amides; C508600:IL6 protein, human; D007375:Interleukin-1; D015850:Interleukin-6; C488421:KRT18 protein, human; D053538:Keratin-18; D014409:Tumor Necrosis Factor-alpha; C570212:sec-butyl-propylacetamide; C045179:valnoctamide; D014635:Valproic Acid; D007371:Interferon-gamma
keywords: ADR; Apoptosis; C reactive protein; CRP; Drug-induced liver damage; HSR; HepG2; Hypersensitivity syndrome; IFN; IL; Mitochondria; SD; SE; SPD; TNF; VCD; VPA; Valproic acid derivatives; adverse drug reaction; hypersensitivity syndrome reaction; interferon; interleukin; sec-Butyl-propylacetamide; standard deviation; status epilepticus; tumor necrosis factor; valnoctamide; valproic acid