High affinity inhibition of Ca(2+)-dependent K+ channels by cytochrome P-450 inhibitors.
The Ca(2+)-dependent K+ channel of human red cells was inhibited with high affinity by several imidazole antimycotics which are potent inhibitors of cytochrome P-450. IC50 values were (in microM): clotrimazole, 0.05; tioconazole, 0.3; miconazole, 1.5; econazole, 1.8. Inhibition of the channel was also found with other drugs with known cytochrome P-450 inhibitory effect. However, no inhibition was obtained with carbon monoxide (CO). This suggests that, given the high selectivity of the above inhibitors for the heme moiety, a different but closely related to cytochrome P-450 kind of hemoprotein may be involved in the regulation of the red cell Ca(2+)-dependent K+ channel. Clotrimazole also inhibited two other charybdotoxin-sensitive Ca(2+)-dependent K+ channels, those of rat thymocytes (IC50 = 0.1-0.2 microM) and of Ehrlich ascites tumor cells (IC50 = 0.5 microM). Imidazole antimycotics inhibit also receptor-operated Ca2+ channels (Montero, M., Alvarez, J. and García-Sancho, J. (1991) Biochem. J. 277, 73-79). This suggests that both Ca2+ and Ca(2+)-dependent K+ channels might have a similar regulatory mechanism involving a cytochrome.
Alvarez
J
J
Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid, Spain.
Montero
M
M
Garcia-Sancho
J
J
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002286:Carcinoma, Ehrlich Tumor; D002413:Cations, Divalent; D002478:Cells, Cultured; D018999:Charybdotoxin; D065607:Cytochrome P-450 Enzyme Inhibitors; D004912:Erythrocytes / Q000378:metabolism / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology*; D008027:Light; D008564:Membrane Potentials; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D012542:Scattering, Radiation; D012604:Scorpion Venoms / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured
D000935:Antifungal Agents; D002413:Cations, Divalent; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D015221:Potassium Channels; D012604:Scorpion Venoms; D018999:Charybdotoxin; D002118:Calcium