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The interaction of liposomal amphotericin B and serum lipoproteins within the biological milieu
1Department of Clinical Investigations, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Abstract:
Previously, we have shown that liposomal amphotericin B (L-AmpB) is less nephrotoxic than and equally as effective as free AmpB as treatment of patients with systemic fungal infections; The mechanism of L-AmpB's enhanced therapeutic index, however, remains unknown. This review discusses AmpB's association with lipoproteins, predominantly high-density lipoproteins (HDL) and the biological relevance of transferring AmpB to HDL. We observed that AmpB was less toxic to pig kidney cells when associated with HDL but still remains toxic when associated with low-density lipoproteins (LDL). AmpB's association with HDL or LDL does not alter its antifungal activity. We further found that these kidney cells express high- and low-affinity LDL receptors but only low-affinity HDL receptors. The reduced renal cytotoxicity of HDL-associated AmpB may be due to its lack of interaction with the renal cells, since they have no HDL receptors. Since AmpB interacts with cholesteryl esters in serum, whose transfer between HDL and LDL is regulated by lipid transfer protein (LTP), we addressed the role of this protein on the distribution of AmpB between HDL and LDL. The addition of LTP altered the lipoprotein distribution of AmpB but not of L-AmpB. Furthermore L-AmpB, but not AmpB (except at 20 micrograms/ml), inhibited the LTP-mediated transfer of cholesterol esters from HDL to LDL. It appears therefore, that the decreased nephrotoxicity associated with L-AmpB administration is related to its predominant distribution to HDL, which is regulated by inhibiting of LTP-mediated cholesterol esters transfer activity.
Insights
Liposomal amphotericin B (L-AmpB) shows reduced kidney toxicity by primarily binding to high-density lipoproteins (HDL). This binding limits interaction with kidney cells, unlike free amphotericin B (AmpB) associated with low-density lipoproteins (LDL).
Area of Science:
- Pharmacology
- Lipid Metabolism
- Nephrology
Background:
- Liposomal amphotericin B (L-AmpB) offers an improved therapeutic index over conventional amphotericin B (AmpB) for systemic fungal infections, but the underlying mechanisms are not fully understood.
- AmpB's interaction with lipoproteins, particularly high-density lipoproteins (HDL) and low-density lipoproteins (LDL), is implicated in its toxicity and efficacy.
Purpose of the Study:
- To investigate the mechanism behind L-AmpB's reduced nephrotoxicity.
- To explore the role of lipoproteins and lipid transfer protein (LTP) in AmpB distribution and renal cell interaction.
Main Methods:
- Assessing AmpB toxicity to pig kidney cells in association with HDL and LDL.
- Evaluating the effect of lipid transfer protein (LTP) on AmpB distribution between HDL and LDL.
- Investigating the expression of HDL and LDL receptors on renal cells.
Main Results:
- AmpB associated with HDL demonstrated reduced toxicity to kidney cells compared to AmpB associated with LDL.
- Kidney cells express high-affinity LDL receptors but only low-affinity HDL receptors, potentially explaining reduced HDL-associated AmpB nephrotoxicity.
- L-AmpB inhibited LTP-mediated cholesterol ester transfer from HDL to LDL, unlike free AmpB.
Conclusions:
- The reduced nephrotoxicity of L-AmpB is likely due to its preferential distribution to HDL, which has limited interaction with renal cells.
- Inhibition of LTP-mediated cholesterol ester transfer by L-AmpB contributes to its favorable lipoprotein distribution and decreased renal toxicity.