Abstract
Valproic acid (VPA) is a widely-used anticonvulsant and mood-stabilizing agent. VPA is also known to inhibit histone deacetylases (HDACs) affecting the expression of numerous genes. In the present study, we examined the effect of VPA on the extracellular signal-related kinase (ERK, p42/p44) pathway (Ras-Raf-MEK-ERK) belonging to the mitogen-activated protein kinases (MAPKs) pathways in primary human hepatocytes. In the liver, the pathway is associated with progression of hepatocellular carcinoma. We found that VPA in a therapeutically relevant concentration (500 µM) activates the ERK pathway, as indicated by increased ERK Thr202/Tyr204 phosphorylation. Interestingly, a prototype HDAC inhibitor, trichostatin A, also activated ERK phosphorylation in primary human hepatocytes. These data suggest that HDAC inhibition might be the primary stimulus for ERK pathway activation in primary human hepatocytes. Notably, U0126, a MEK1 inhibitor, was ineffective in inhibiting ERK pathway activation, likely due to its metabolic deactivation in metabolically competent primary human hepatocytes. We conclude that VPA activates the ERK pathway in primary human hepatocytes.
Highlights
Valproic acid (VPA) has been used in the treatment of epilepsy for almost 40 years[1]
In three independent primary human hepatocyte cultures, we examined the effects of VPA (500 μM), trichostatin A (TSA) (100 nM) and MEK1 inhibitor U0126 (10 μM) on extracellular signal-regulated kinase (ERK) pathway activation
We found that VPA activates phosphorylation of ERK in all three primary human hepatocyte cultures (Fig. 1)
Summary
Valproic acid (VPA) has been used in the treatment of epilepsy for almost 40 years[1] It is used for its anti-seizure activity, as well as in the treatment of migraine and bipolar disorders[2,3]. VPA is a welltolerated drug, hepatotoxicity[7,8,9], bone marrow suppression[10], decreased bone cell production, and osteomalacia are some of its adverse effects[11]. Even though it is extremely rare, the potential hepatotoxicity resulting in fatal liver failure is of major concern in treating patients with valproate[12,13]. In addition to the hepatotoxicity, VPA is a human teratogen[14]
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