title: Cytotoxicity induced by the combination of valproic acid and tumor necrosis factor-alpha: implication for valproic acid-associated hepatotoxicity syndrome.
abstract: A previous study showed that valproic acid (VPA) and tumor necrosis factor-alpha (TNF-alpha) exhibit synergistic toxicity (lethality) in Sprague-Dawley and Wistar rats. The present study investigated a possible mechanism for this synergy using an in vitro system. Incubation of human U937 cells with 1 mM VPA or with 0.001 ng/mL of TNF-alpha alone had a negligible effect on cytotoxicity (less than 7%). However, the combination of the two drugs significantly increased the cytotoxicity up to 34%. Chronic treatment of U937 cells with VPA or TNF-alpha for 48 hr reduced protein kinase C (PKC) activity. Further, the PKC selective inhibitor Gö6976 potentiated VPA-induced cytotoxicity and TNF-alpha-induced cytotoxicity, whereas the PKC activator phorbol-12-myristate-13-acetate provided a significant protection against the cytotoxicity associated with VPA or TNF-alpha. These results suggest that the synergism in cytotoxicity exhibited by the combination of VPA and TNF-alpha may be mediated through attenuation of PKC activity.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle 98195-7610, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Yao
authors.forename: G G
authors.initials: GG
authors.lastname: Mather
authors.forename: J R
authors.initials: JR
authors.lastname: Stephens
authors.forename: R H
authors.initials: RH
authors.lastname: Levy
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000633:toxicity; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D020298:U937 Cells; D014635:Valproic Acid / Q000633:toxicity*
chemical_list: D000927:Anticonvulsants; D003603:Cytotoxins; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D014635:Valproic Acid; D011493:Protein Kinase C