Polyene
antibiotic administration is limited by dose-dependent nephrotoxicity. The latter is believed to be mediated by polyene anchoring to plasma membrane
cholesterol, resulting in pore formation, abnormal ion/solute flux,
adenosine triphosphate (
ATP) declines, and, ultimately, a loss of tubule viability. The relative nephrotoxicity of these agents and their liposomal preparations has remained poorly defined. Thus, freshly isolated mouse proximal tubules or cultured human proximal tubule (HK-2) cells were exposed to either
nystatin,
amphotericin B, or three different polyene liposomal preparations (Nyotran,
AmBisome, or
Abelcet; 4 to 64 microg/mL). The impact of these agents on (1) plasma membrane injury (
sodium-driven
ATP consumption, assessed by
ATP-
adenosine diphosphate [
ADP] ratios); (2) cellular susceptibility to superimposed injury (chemical
hypoxia or
ferrous ammonium sulfate-mediated oxidative stress; assessed by
lactate dehydrogenase release); and (3) membrane
cholesterol,
phospholipid, and
ceramide expression was assessed.
Amphotericin B was more cytotoxic than
nystatin (approximately 25% to 50% greater
ATP-
ADP ratio declines). Most of this toxicity could be eliminated by polyene liposomal formulation. Nevertheless, the liposomal
polyenes still fully sensitized tubule cells to superimposed chemical hypoxic (
antimycin/
deoxyglucose), but not
oxidant, attack.
Nystatin and
amphotericin B caused acute increments in tubule
sphingomyelin-
phosphatidylcholine ratios and
ceramide content (indicating an impact on the plasma membrane extending beyond the classic view of pore formation with ion flux). In conclusion, (1)
nystatin is seemingly less cytotoxic than
amphotericin B (in contrast to the prevailing clinical view); (2) liposomal formulation markedly decreases this cytotoxicity; (3) despite this reduced toxicity, liposomal
polyenes are still able to render tubule cells more vulnerable to selected forms of superimposed injury; and (4) acute alterations in plasma membrane
phospholipid and
ceramide expression are previously unrecognized consequences and potential mediators of polyene-mediated tubular cell attack.