The effect of the phenol compound ellagic acid on Ca2+ homeostasis and cytotoxicity in liver cells

Ellagic acid, a natural phenol compound found in numerous fruits and vegetables, causes various physiological effects in different cell models. However, the effect of this compound on Ca2+ homeostasis in liver cells is unknown. This study examined the effect of ellagic acid on intracellular [Ca2+](i) concentration ([Ca2+],) and established the relationship between Ca2+ signaling and cytotoxicity in liver cells. The data show that ellagic acid induced concentration-dependent [Ca2+](i), rises in HepG2 human hepatoma cells, but not in HA22T, HA59T human hepatoma cells or AML12 mouse hepatocytes. In HepG2 cells, this Cat' signal response was reduced by removing extracellular Ca2+ and was inhibited by store-operated Cat' channel blockers (2-APB, econazole or SKF96365) and the protein kinase C (PKC) inhibitor GF109203X. In Cat-'-free medium, pretreatment with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin abolished ellagic acid-induced [Ca2+](i), rises. Conversely, incubation with ellagic acid abolished thapsigargin-induced [Ca2+](i), rises. Inhibition of phospholipase C (PLC) with U73122 also abolished ellagic acid induced [Ca2+](i), rises. Ellagic acid (25-100 M) concentration-dependently caused cytotoxicity in HepG2, HA22T or HA59T cells, but not in AML12 cells. Furthermore, this cytotoxic effect was partially prevented by prechelating cytosolic Ca2+ with BAPTA-AM only in HepG2 cells. Together, in HepG2 cells, ellagic acid induced [Ca2+](i), rises by inducing PLC-dependent [Ca2+](i) release from the endoplasmic reticulum and [Ca2+](i) entry via PKC-sensitive store-operated [Ca2+](i) channels. Moreover, ellagic acid induced [Ca2+](i)-associated cytotoxicity. (C) 2016 Elsevier B.V. All rights reserved.