Mechanism of amphotericin B stimulation of net calcium efflux from neonatal mouse calvariae.
Amphotericin B is a polyene antifungal agent that binds to membrane sterols, creating aqueous pores that permit ion fluxes sufficient to cause cell lysis. It has also been shown to alter ion transport in mammalian cells, including proton secretion from renal tubular cells. The latter effect can lead to distal renal tubular acidosis in patients treated for systemic fungal infections. Based on the understanding that osteoclast-mediated bone resorption is dependent on proton secretion, we examined the effect of amphotericin B on calcium efflux from neonatal mouse calvariae in organ culture. Amphotericin B (5 micrograms/ml) stimulated net calcium efflux from calvariae within 24 h to a level almost as great as that produced by a maximally effective concentration of parathyroid hormone. The stimulated calcium efflux was completely inhibited by both 10 ng/ml salmon calcitonin, a physiologic inhibitor of osteoclast activity, and 4 x 10(-4) M acetazolamide, a specific inhibitor of carbonic anhydrase, the enzyme necessary for substantial proton generation by osteoclasts. These results indicate a direct effect of amphotericin B on bone in vitro to stimulate osteoclast-mediated calcium efflux.
Nephrology Section, Pritzker School of Medicine, University of Chicago, IL 60637.
N F
NF
Blair
N S
NS
Krieger
D A
DA
Bushinsky
D000086:Acetazolamide / Q000494:pharmacology; D000666:Amphotericin B / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D001862:Bone Resorption / Q000139:chemically induced / Q000188:drug therapy; D002116:Calcitonin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D046508:Culture Techniques; D051379:Mice; D012886:Skull / Q000187:drug effects* / Q000378:metabolism
D000666:Amphotericin B; D002116:Calcitonin; D000086:Acetazolamide; D002118:Calcium