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PERTURBATION OF VOLTAGE-SENSITIVE Ca2+ CHANNEL FUNCTION BY VOLATILE ORGANIC SOLVENTS.
SHAFER, T. J., P. J. BUSHNELL, V. A. BENIGNUS, AND J. J. WOODWARD. PERTURBATION OF VOLTAGE-SENSITIVE Ca2+ CHANNEL FUNCTION BY VOLATILE ORGANIC SOLVENTS. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD, 315(3):1109-1118, (2005).
The mechanisms underlying the acute neurophysiological and behavioral effects of volatile organic compounds (VOCs) remain to be elucidated. However, the function of neuronal ion channels is perturbed by VOCs. The present study examined effects of toluene (TOL), trichloroethylene (TCE), and perchloroethylene (PERC) on whole-cell calcium current (ICa) in nerve growth factor-differentiated pheochromocytoma (PC12) cells. All three VOCs affected ICa in a reversible, concentration-dependent manner. At +10-mV test potentials, VOCs inhibited ICa, whereas at test potentials of -20 and -10 mV, they potentiated it. The order of potency for inhibition (IC50) was PERC (270 microM) > TOL (720 microM) > TCE (1525 microM). VOCs also changed ICa inactivation kinetics from a single- to double-exponential function. Voltage-ramp experiments suggested that VOCs shifted ICa activation in a hyperpolarizing direction; this was confirmed by calculating the half-maximal voltage of activation (V1/2, act) in the absence and presence of VOCs using the Boltzman equation. V(1/2, act) was shifted from approximately -2 mV in control to -11, -12, and -16 mV by TOL, TCE, and PERC, respectively. Similarly, VOCs shifted the half-maximal voltage of steady-state inactivation (V1/2, inact) from approximately -16 mV in control to -32, -35, and -20 mV in the presence of TOL, TCE, and PERC, respectively. Inhibition of ICa by TOL was confirmed in primary cultures of cortical neurons, where 827 microM TOL inhibited current by 61%. These data demonstrate that VOCs perturb voltage-sensitive Ca2+ channel function in neurons, an effect that could contribute to the acute neurotoxicity of these compounds.
This manuscript characterizes the mechanism of action of toluene on voltage-sensitive calcium channels in neuronal cells. " This manuscript also presents novel data that provides a plausible mechanism, disruption of ion channel function,by which trichloroethylene and perchloroethylene (1,1,1,1-trichloroethylene) may produce acute neurotoxic effects. " The relative potencies of effects of toluene, trichloroethylene and perchloroethylene reported in these in vitro studies are consistent with their relative in vivo potencies. Furthermore, effects occur in vitro at concentrations that are relative to estimated in vivo brain levels for these compounds. " This information provides a plausible target site in neurons for effects of VOCs, and demonstrates the validity of using in vitro techniques to examine modes of action of volatile organic compounds.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
NEUROPHYSIOLOGICAL TOXICOLOGY BRANCH