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Inhibition of voltage‐gated Ca 2+ entry into GH 3 and chromaffin cells by imidazole antimycotics and other cytochrome P450 blockers
Author(s) -
Villalobos Carlos,
Fonteriz Rosalba,
Lopez Manuela G.,
Garcia Antonio G.,
GarciaSancho Javier
Publication year - 1992
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.6.9.1319362
Subject(s) - clotrimazole , chemistry , econazole , cytochrome p450 , stereochemistry , biophysics , biochemistry , ketoconazole , biology , enzyme , antifungal , microbiology and biotechnology
We have studied the effects of cytochrome P450 inhibitors on the entry of Ca 2 ∗ and Mn 2 ∗, used here as a Ca 2 ∗ surrogate for Ca 2+ channels, in fura‐2‐loaded GH 3 pituitary cells and bovine chromaffin cells depolarized with high‐K∗ solutions. Imidazole antimycotics were potent inhibitors (econazole > miconazole > clotrimazole > ketoconazole). α ‐Naphtoflavone and isosafrole, but not metyrapone, also inhibited the entry of Ca 2 ∗ and Mn 2 ∗ induced by depolarization. This inhibitory profile most resembles that reported for IA‐type cytochrome P450. However, carbon monoxide (CO), a well‐known cytochrome P450 antagonist, had no effect on Ca 2+ (Mn 2+ ) entry. Given the high selectivity of the imidazole antimycotics for the heme moiety, our results suggest that a hemoprotein closely related to cytochrome P450 (but insensitive to CO) might be involved in the regulation of voltage‐gated Ca 2+ channels. The inhibitory pattern was also similar to that previously reported for agonist‐induced Ca 2+ (Mn 2+ ) influx in neutrophils and platelets, although CO was an efficient inhibitor in this case. These results pose the question of whether similarities in the sensitivity to cytochrome P450 inhibitors exhibited by receptor‐operated and voltage‐gated channels reflect unknown similarities either in structural features or regulation mechanisms.— Villalobos, C.; Fonteriz, R. Lopez, M. G.; Garcia, A. G.; Garcia‐Sancho, J. Inhibition of voltage‐gated Ca 2+ entry into GH 3 and chromaffin cells by imidazole antimycotics and other cytochrome P450 blockers. FASEB J. 6: 2742‐2747; 1992.