Gallic acid, a metabolite of the antioxidant propyl gallate, inhibits gap junctional intercellular communication via phosphorylation of connexin 43 and extracellular-signal-regulated kinase1/2 in rat liver epithelial cells.
Propyl gallate and its metabolite, gallic acid, are widely used as antioxidants in the food industry, but they have been shown to exhibit liver toxicity and enhance carcinogenesis. In the present study, we investigated the possible undesirable effects of propyl gallate and gallic acid on gap junctional intercellular communication (GJIC), inhibition of which is closely linked to carcinogenesis. Gallic acid and propyl gallate exhibited dose-dependent free-radical-scavenging activities as determined by 1,1-diphenyl-2-picrylhydrazyl- or 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)-radical-scavenging assays, and the free-radical-scavenging activity of gallic acid was stronger than that of propyl gallate. However, using WB-F344 rat liver epithelial cells, gallic acid inhibited GJIC in a dose-dependent manner, while propyl gallate had no significant effect compared with untreated controls. The gallic-acid-induced inhibition of GJIC was reversible, with a recovery of nearly 65% after 120 min. Gallic acid induced the phosphorylation of connexin 43 (Cx43) and phosphorylation of extracellular-signal-regulated kinase1/2 (ERK1/2). The gallic-acid-induced inhibition of GJIC was attenuated by treatment with mitogen-activated protein kinase kinase inhibitors (U0126 and PD098059). U0126 blocked the gallic-acid-induced phosphorylation of Cx43 and ERK1/2, indicating that the gallic-acid-induced inhibition of GJIC is mediated by phosphorylation of Cx43 via activation of ERK1/2. In addition, gallic-acid-induced inhibition of GJIC was protected by ascorbic acid and quercetin, which might represent a simple example of the different effects of natural antioxidants in carcinogenesis.
Kim
Jong Hun
JH
Department of Agricultural Biotechnology and Center for Agricultural Biomaterials, Seoul National University, Seoul 151-921, Republic of Korea.
Kang
Nam Joo
NJ
Lee
Bo Kyung
BK
Lee
Ki Won
KW
Lee
Hyong Joo
HJ
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects*; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D005609:Free Radicals / Q000378:metabolism; D005707:Gallic Acid / Q000494:pharmacology*; D017629:Gap Junctions / Q000187:drug effects*; D008099:Liver / Q000166:cytology* / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D011435:Propyl Gallate / Q000378:metabolism*; D011794:Quercetin / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction
D018031:Connexin 43; D005609:Free Radicals; C012526:quercitrin; D005707:Gallic Acid; D011435:Propyl Gallate; D011794:Quercetin; D048052:Mitogen-Activated Protein Kinase 3; D001205:Ascorbic Acid