Differential effects of organotin compounds on voltage-gated potassium currents in lymphocytes and neuroblastoma cells.
Effects of organotin compounds were studied on voltage-gated K+ current in whole-cell voltage clamped lymphocytes and in N1E-115 neuroblastoma cells. In human peripheral blood lymphocytes the immunotoxic compounds dibutyltinchloride (DBT, 2.5 microM) and triphenyltinchloride (TPhT, 2.5 microM) decrease the peak amplitude of the K+ current and prolong time to peak. Tributyltinchloride (TBT, 2.5 microM) decreases the K+ current to a greater extent than DBT and TPhT, without affecting the time to peak. The neurotoxic organotin compound trimethyltinchloride (TMT, 2.5 microM) does not affect the voltage-gated K+ current in lymphocytes. Similar effects of DBT were observed in freshly isolated and PHA-activated human lymphocytes and with rat thymocytes. On the other hand, in mouse N1E-115 neuroblastoma cells, none of the organotin compounds altered the voltage-dependent K+ current. In human lymphocytes DBT affects both the peak amplitude and the time to peak of the K+ current in a concentration-dependent manner. At the maximum concentration of 10 microM tested, the peak amplitude of the K+ current was reduced to 22 +/- 4% of the control current. The IC50 and slope factor for block of the peak outward current by DBT amounts to 6.7 +/- 0.4 microM, and 2.7 +/- 0.4, respectively. The delay in K+ current activation does not saturate. At 10 microM DMT increases the time to peak to 332 +/- 12% of the control value. The present results suggest that the effects by DBT originate from two separate interactions with the voltage-gated K+ channel at the extracellular site of the membrane: a direct effect on the closed K+ channel causing a delay in current activation and a membrane-related effect causing inhibition of the K+ current. The differential effects of the organotin compounds may relate to their differential toxicological action.
Oortgiesen
M
M
Research Institute of Toxicology, Utrecht University, Netherlands.
Visser
E
E
Vijverberg
H P
HP
Seinen
W
W
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy*; D009947:Organotin Compounds / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
D009947:Organotin Compounds; D015221:Potassium Channels