Potential role of the low-density lipoprotein receptor family as mediators of cellular drug uptake
Introduction
Lipoproteins are biological carriers in which lipids and proteins can be transported systemically. It is well established that specific drugs such as halofantrine (Hf), amphotericin B (AmpB) and cyclosporine A (CsA) associate with lipoproteins [9], [10], [11]. Therefore, by understanding the mechanism in which these lipoprotein-bound drugs can be taken up intracellularly may provide novel methods in drug targeting. There have been a number of studies suggesting that the LDL receptor and members of its superfamily may be playing a role in cellular drug uptake, specifically, aminoglycosides, type-I ribosome-inactivating proteins (RIP), anionic liposomes and cyclosporine A. Therefore, it would be of interest to examine the role of the LDL receptor family as a mechanism of cellular drug uptake.
Section snippets
Lipoproteins and their metabolism
Lipoproteins are a class of complex macromolecules consisting of both lipid and protein subgroups. Their main responsibility is to transport a number of water insoluble nutrients throughout the systemic circulation, mainly lipids in an aqueous environment. Lipoproteins are characterized by an insoluble core of cholesteryl ester and triglyceride surrounded by a shell of amphipathic phospholipids and specialized proteins called apolipoproteins [1], [2] (Fig. 1). They differ in their content of
Drug binding with lipoproteins
Plasma lipoproteins are primarily involved in the transport of lipids and proteins throughout systemic circulation. However, the biological significance of lipoproteins extends beyond lipid transport to the transport of hydrophobic drugs. Drugs such as CsA [9], Hf [11] and amphotericin B lipid complex (ABLC) [10] have been shown to associate extensively with plasma lipoproteins. These drugs have pharmacokinetic properties, tissue distribution and pharmacological activities that are affected by
The LDL receptor and its family members
The LDL receptor is an endocytic receptor that transports relevant macromolecules, mainly the cholesterol-rich lipoprotein LDL, into cells through a process called receptor-mediated endocytosis [54] (see Fig. 2). This process involves the cell surface receptor recognizing an LDL particle from the extracellular membrane (ECM), internalizing it through clathrin-coated pits and transporting it intracellularly via a vesicle [54], [55], [56]. Subsequently, the vesicle becomes degraded upon fusion
Drug interactions with LDL receptor family members
Recent studies have suggested the role of the LDL receptor family in the cellular uptake of drugs, including aminoglycosides, type-I ribosome inactivating protein, lipid-based formulations and cyclosporine A.
Conclusions
It is well established that certain drugs associate with lipoproteins. Thus lipoproteins can act as a natural drug delivery system for hydrophobic drugs or lipid-based formulations. Nevertheless, it is the association of these drugs with lipoproteins that may be able to explain their pharmacological activity, pharmacokinetic properties as well as its toxicities. Furthermore, by understanding the uptake mechanisms of these specific drug delivery systems, it can provide better therapeutic
Acknowledgements
We would like to acknowledge Kathy (Peteherych) Boulanger for contributing the diagrams from her thesis to this manuscript. Thank you to Dr. Kristina Sachs-Barrable for helping to review and for providing suggestions. In addition, we would like to thank the Canadian Institutes of Health Research (MOP #14484 to KMW) for the many years of funding.
References (148)
- et al.
Structure, assembly and secretion of lipoproteins
- et al.
Molecular physiology of reverse cholesterol transport
J. Lipid Res.
(1995) - et al.
Dynamics of lipoprotein transport in the human circulatory system
High-density lipoprotein metabolism
J. Lipid Res.
(1984)Modification in plasma lipoprotein concentration and lipid composition regulate the biological activity of hydrophobic drugs
J. Pharmacol. Toxicol. Methods
(1996)- et al.
Lancet
(1986) Renal effects of cyclosporine
J. Am. Acad. Dermatol.
(1990)- et al.
Efficacy of multiple does-halofantrine in the treatment of chloroquine resistant faciparum malaria in Kenya
Lancet
(1988) - et al.
Alterations in lecithin–cholesterol acyltransferase activity during Plasmodium chabaudi rodent malaria
Biochimie
(1985) - et al.
Differences in the lipoprotein distribution of halofantrine are regulated by lipoprotein apolar lipid and protein concentration and lipid transfer protein I activity: in vitro studies in normlipidemic and dyslipidemic human plasmas
J. Pharm. Sci.
(1999)
Differences in the lipoprotein binding profile of halofantrine in fed and fasted human or beagle plasma are dictated by the respective masses of core apolare lipoprotein lipid
J. Pharm. Sci.
The influence of lipid on stereoselective pharmacokinetics of halofantrine: important implications in food-effect studies involving drugs that bind to lipoproteins
J. Pharm. Sci.
Preferential distribution of amphotericin B lipid complex into human HDL3 is a consequence of high density lipoprotein coat lipid content
J. Pharm. Sci.
Heat-induced superaggregation of amphotericin B modifies its interaction with serum proteins and lipoproteins and stimulation of TNF-alpha
J. Pharm. Sci.
The human LDL receptor: a cysteine-rich protein with multiple alu sequences in its mRNA
Cell
The very low density lipoprotein receptor: a second lipoprotein receptor that may mediate uptake of fatty acids into muscle and fat cells
Trends Cardiovasc. Med.
Very low density lipoprotein receptor binds and mediates endocytosis of urokinase-type plasminogen activator-type-1 plasminogen activator inhibitor complex
J. Biol. Chem.
Human apolipoprotein E receptor 2: a novel lipoprotein receptor of the low density lipoprotein receptor family predominantly expressed in the brain
J. Biol. Chem.
A new low-density lipoprotein receptor homologue with 8 ligand binding repeats in brain of chicken and mouse
J. Biol. Chem.
Role of reelin in the control of brain development
Brain Res. Brain Res. Rev.
Reeler/disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and apoE receptor 2
Cell
The LDL receptor gene family: (un)expected signal transducers in the brain
Neuron
The second and fourth cluster of class A cysteine-rich repeats of the low density lipoprotein receptor-related protein share ligand-binding properties
J. Biol. Chem.
The putative tumor suppressor LRP1b, a novel member of the low-density lipoprotein (LDL) receptor family, exhibits both overlapping and distinct properties with the LDL receptor-related protein
J. Biol. Chem.
Low density lipoprotein (LDL) receptor-related protein 1b impairs urokinase receptor regeneration on the cell surface and inhibits cell migration
J. Biol. Chem.
Identification of high-molecular-weight proteins with multiple EGF-like motifs by motif-trap screening
Genomics
Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family
Biochem. Biophys. Res. Commun.
Molecular cloning and characterization of LR3, a novel LDL receptor family protein with mitogenic activity
Biochem. Biophys. Res. Commun.
Cloning of a novel member of the low-density lipoprotein receptor family
Gene
Wg/Wnt signal can be transmitted through arrow/LRP5,6 and axin independently of Zw3/Gsk3beta activity
Dev. Cell
Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway
Mol. Cell
LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development
Cell
Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density
Am. J. Hum. Genet.
Mesd encodes and LRP5/6 chaperone essential for specification of mouse embryonic polarity
Cell
Molecular characterization of a novel human hybrid-type receptor that binds the alpha2-macroglobulin receptor-associated protein
J. Biol. Chem.
Differentail exression of LR11 during proliferation and differentiation of cultured neuroblastoma cells
Biochem. Biophys. Res. Commun.
Elements of neural adhesion molecules and a yeast vacuolar protein sorting receptor are present in a novel mammalian low density lipoprotein receptor family member
J. Biol. Chem.
Lipoproteins in health and disease: lipoprotein nomenclature and the classification of hyperlipoproteinemia
Role of plasma lipoproteins in modifying the biological activity of hydrophobic drugs
J. Pharm. Sci.
Lipoprotein structure
The biochemistry of lipoproteins
J. Inherit. Metab. Dis.
Relation of cyclosporine blood levels to adverse effects on lipoproteins
Transplantation
Characteristics of lipid-based formulations that influence their biological behaviour within the plasma of patients
Clin. Infect. Dis.
The degree of association of halofantrine with pre- and post-prandial plasma lipoproteins is determined by their apolar lipid content
Pharm. Res.
The pharmacokinetics of cyclosporine: blood plasma distribution and binding studies
Drug Metab. Dispos.
Effects of plasma lipid levels on blood distribution and pharmacokinetics of cyclosporine A
Ther. Drug Monit.
Interaction of cyclosporine A with human lipoproteins
J. Pharm. Pharmacol.
Serum cholesterol levels and kidney transplantation outcome: attenuation of cyclosporine efficacy?
Transplant
Differences in lipoprotein lipid concentration and composition modify the plasma distribution of cyclosporine
Pharm. Res.
Influence of blood components on the tissue uptake indices of cyclosporine in rats
J. Pharmacol. Exp. Ther.
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