Cytotoxicity induced by the combination of valproic acid and tumor necrosis factor-α: Implication for valproic acid-associated hepatotoxicity syndrome

A previous study showed that valproic acid (VPA) and tumor necrosis factor-α (TNF-α) 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-α 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-α for 48 hr reduced protein kinase C (PKC) activity. Further, the PKC selective inhibitor Gö6976 potentiated VPA-induced cytotoxicity and TNF-α-induced cytotoxicity, whereas the PKC activator phorbol-12-myristate-13-acetate provided a significant protection against the cytotoxicity associated with VPA or TNF-α. These results suggest that the synergism in cytotoxicity exhibited by the combination of VPA and TNF-α may be mediated through attenuation of PKC activity.