Induction of interleukin-1beta, tumour necrosis factor-alpha and apoptosis in mouse organs by amphotericin B is neutralized by conjugation with arabinogalactan.
OBJECTIVE
To investigate the possibilities that: (i) organ toxicity of amphotericin B-deoxycholate (AMB-DOC) is related to induction of interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and apoptosis in target organs; and (ii) the reduced toxicity resulting from the conjugation of AMB with water-soluble arabinogalactan (AMB-AG), is related to modulation of these parameters.


METHODS
Organ expression of IL-1beta and TNF-alpha was evaluated by enzyme-linked immunosorbent assay (ELISA) in mouse organ biological fluids and in situ by immunohistochemistry. Tissue damage was evaluated histologically, and apoptosis was demonstrated by terminal dUTP nick end-labelling (TUNEL) staining. AMB-AG conjugate was compared with the micellar (AMB-DOC) and liposomal (AmBisome) AMB formulations.


RESULTS
Treatment with AMB-AG or AmBisome caused no observable histopathological damage in the kidneys. In contrast, treatment with AMB-DOC resulted in disruptive changes and apoptosis in renal tubular cells. These effects were found to correlate with induction of high levels of IL-1beta and TNF-alpha in kidney lysates. Unlike AMB-AG, AMB-DOC also induced enhanced IL-1beta and TNF-alpha expression in lysates of lungs, brain, liver and spleen. The marked elevation of these inflammation-apoptosis-promoting cytokines after treatment with AMB-DOC may mediate its systemic and local renal damage. Treatment with AMB-AG (but not AmBisome) appears to uniquely modulate the in situ expression of IL-1beta and enhance secretion of TNF-alpha in kidneys, effects possibly involved in prevention of apoptosis.


CONCLUSIONS
AMB-related toxicity is associated with induction of IL-1beta, TNF-alpha and apoptosis in organs. These effects were not observed with AMB-AG conjugate, suggesting its potential as a safer formulation for therapy.
Falk
Rama
R
Department of Clinical Microbiology and Infectious Diseases, The Hebrew University-Hadassah Medical Center, PO Box 12000, Jerusalem 91120, Israel.
Hacham
Moshe
M
Nyska
Abraham
A
Foley
Julie F
JF
Domb
Abraham J
AJ
Polacheck
Itzhack
I
D000666:Amphotericin B / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism; D003840:Deoxycholic Acid / Q000008:administration & dosage; D004338:Drug Combinations; D005685:Galactans / Q000737:chemistry*; D007375:Interleukin-1 / Q000096:biosynthesis; D007668:Kidney / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000935:Antifungal Agents; D016207:Cytokines; D004338:Drug Combinations; D005685:Galactans; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; C068538:liposomal amphotericin B; D003840:Deoxycholic Acid; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; C005653:arabinogalactan