Effect of nordihydroguaiaretic acid on intracellular Ca2+ concentrations in hepatocytes

The effect of nordihydroguaiaretic acid (NDGA) on Ca2+ signaling in human hepatoma cells (HA22/VGH) has been investigated. NDGA (5-50 muM) increased [Ca2+](i) concentration-dependently. The [Ca2+](i) increase comprised an initial rise and an elevated phase over a time period of 4 min. Removal of extracellular Ca2+ reduced 10-50 muM NDGA induced [Ca2+](i) signals by 45 +/- 5%. Consistently, the 50 muM NDGA-induced [Ca2+](i) increase in Ca2+-containing medium was reduced by 41 +/- 2% by 10 muM of La3+, nifedipine or verapamil. In Ca2+-free medium, pretreatment with 20 muM NDGA for 6 min abolished the [Ca2+](i) increase induced by the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin (1 muM). Conversely, 20 muM NDGA failed to increase [Ca2+](i) after 1 muM thapsigargin had depleted the endoplasmic reticulum Ca2+ store. Inhibition of phospholipase C with 2 muM U73122 had little effect on 20 muM NDGA-induced Ca2+ release. Several other lipoxygenase inhibitors had no effect on basal [Ca2+](i). Together, the data suggest that NDGA increased [Ca2+](i) in hepatocytes in a lipoxygenase-independent manner, by releasing Ca2+ from the endoplasmic reticulum and causing Ca2+ influx. (C) 2002 Elsevier Science Ltd. All rights reserved.