Nordihydroguaiaretic acid depletes atp and inhibits a swelling
-activated, atp-sensitive taurine channel.
Wang, Nazzareno Ballatori Wei.
Department of Environmental Medicine, University of Rochester
School of Medicine, Rochester, NY 14642
APStracts 3:0406C, 1996.
The mechanism by which nordihydroguaiaretic acid (NDGA), a
lipoxygenase inhibitor, prevents swelling-activated organic osmolyte
efflux was examined in the human hepatoma cell line HepG2. When
swollen in hypotonic medium, HepG2 cells exhibited a regulatory
volume decrease (RVD) that was associated with the release of
intracellular taurine, an amino acid found at a concentrations of
22.0+/-2.5 nmol/mg protein (5 mM) in these cells. Rate coefficients
for swelling-activated [3H]taurine uptake and efflux were unaffected
when extracellular taurine was increased from 0.1 to 25 mM,
indicating that taurine is released via a channel. Taurine efflux was
rapidly activated after cell swelling, and immediately inactivated
when cells were returned to normal size by restoring isotonicity.
Swelling-activated taurine efflux was not altered by replacement of
extracellular Na+ with choline+ or K+, but was inhibited when
cellular ATP levels were decreased with a variety of chemical agents,
consistent with an ATP-regulated channel previously described in
other cell types. NDGA inhibited swelling-activated [3H]taurine
efflux in HepG2 cells at concentrations of 50-150 [mu]M; however,
these same concentrations of NDGA also lowered cell ATP levels.
Likewise, ketoconazole, an inhibitor of cytochrome P450
monooxygenases, inhibited [3H]taurine efflux only at concentrations
where cell ATP levels were also lowered. In contrast, other
inhibitors of cyclooxygenase (indomethacin, 100 [mu]M) or of
lipoxygenases (caffeic acid, 100 [mu]M), as well as arachidonic acid
itself (100 [mu]M), had no effect on either taurine efflux or cell
ATP. The present findings characterize a swelling-activated, ATP
-sensitive osmolyte channel in HepG2 cells, and demonstrate that
NDGA's inactivation of the channel is related to its ability to
deplete cellular ATP.
Received 15 October 1996; accepted in final form 3 December 1996.
APS Manuscript Number C590-6.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 31 December 1996