title: The effect of the phenol compound ellagic acid on Ca(2+) homeostasis and cytotoxicity in liver cells.
abstract: 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 Ca(2+) homeostasis in liver cells is unknown. This study examined the effect of ellagic acid on intracellular Ca(2+) concentration ([Ca(2+)]i) and established the relationship between Ca(2+) signaling and cytotoxicity in liver cells. The data show that ellagic acid induced concentration-dependent [Ca(2+)]i rises in HepG2 human hepatoma cells, but not in HA22T, HA59T human hepatoma cells or AML12 mouse hepatocytes. In HepG2 cells, this Ca(2+) signal response was reduced by removing extracellular Ca(2+) and was inhibited by store-operated Ca(2+) channel blockers (2-APB, econazole or SKF96365) and the protein kinase C (PKC) inhibitor GF109203X. In Ca(2+)-free medium, pretreatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin abolished ellagic acid-induced [Ca(2+)]i rises. Conversely, incubation with ellagic acid abolished thapsigargin-induced [Ca(2+)]i rises. Inhibition of phospholipase C (PLC) with U73122 also abolished ellagic acid-induced [Ca(2+)]i rises. Ellagic acid (25-100μM) 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 Ca(2+) with BAPTA-AM only in HepG2 cells. Together, in HepG2 cells, ellagic acid induced [Ca(2+)]i rises by inducing PLC-dependent Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry via PKC-sensitive store-operated Ca(2+) channels. Moreover, ellagic acid induced Ca(2+)-associated cytotoxicity.
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC.
authors.forename: Wei-Zhe
authors.initials: WZ
authors.lastname: Liang
authors.affiliation: Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chia-Yi 613, Taiwan, ROC; Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chia-Yi 613, Taiwan, ROC.
authors.forename: Chiang-Ting
authors.initials: CT
authors.lastname: Chou
authors.affiliation: Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC.
authors.forename: Jin-Shiung
authors.initials: JS
authors.lastname: Cheng
authors.affiliation: Department of Rehabilitation, Kaohsiung Veterans General Hospital Tainan Branch, Tainan 710, Taiwan, ROC.
authors.forename: Jue-Long
authors.initials: JL
authors.lastname: Wang
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC.
authors.forename: Hong-Tai
authors.initials: HT
authors.lastname: Chang
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC.
authors.forename: I-Shu
authors.initials: IS
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC.
authors.forename: Ti
authors.initials: T
authors.lastname: Lu
authors.affiliation: Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC.
authors.forename: Jeng-Hsien
authors.initials: JH
authors.lastname: Yeh
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 907, Taiwan, ROC.
authors.forename: Daih-Huang
authors.initials: DH
authors.lastname: Kuo
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 907, Taiwan, ROC.
authors.forename: Pochuen
authors.initials: P
authors.lastname: Shieh
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 907, Taiwan, ROC.
authors.forename: Fu-An
authors.initials: FA
authors.lastname: Chen
authors.affiliation: Department of Nursing, Tzu Hui Institute of Technology, Pingtung 907, Taiwan, ROC.
authors.forename: Chun-Chi
authors.initials: CC
authors.lastname: Kuo
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC. Electronic address: pseudoo67@gmail.com.
authors.forename: Chung-Ren
authors.initials: CR
authors.lastname: Jan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004610:Ellagic Acid / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D056945:Hep G2 Cells; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D008345:Manganese / Q000378:metabolism; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D004610:Ellagic Acid; D008345:Manganese; D011493:Protein Kinase C; D010738:Type C Phospholipases; D002118:Calcium
keywords: Ca(2+); Cytotoxicity; Ellagic acid; Liver cells; Phenolic compound