Hydroxypropylcyclodextrins in Parenteral use. I: Lipid Dissolution and Effects on Lipid Transfers in Vitro

Irie, Tetsumi; Fukunaga, Kazuhiro; Pitha, Josef

doi:10.1002/jps.2600810609

Cited by 131 publications

(92 citation statements)

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“…High concentrations of Cds have been shown to have limited specificity for cholesterol and to cause significant membrane disorganization in previous studies, consistent with our results (Irie et al, 1992;Ohvo-Rekila et al, 2000;Kiss et al, 2010). However, we observed saturation of ergosterol solubilization for 1:3 and 1:4 Cx:Cd complexes (Figure 1).…”

Section: Discussionsupporting

confidence: 92%

“…Hydrogen bonding is responsible for the tight packing of lipid rafts but still ensures a high degree of lipid mobility (Ohvo-Rekila et al, 1997). The acyl chains between the phospholipids are held together by van der Waals interactions, which are considerably weaker than hydrogen bonds and, therefore, are responsible for looser packing of prokaryotic membranes and non-lipid raft portions of eukaryotic cell membranes (Irie et al, 1992;Barman et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Renal toxicity of a-Cd and b-Cd after parenteral administration, as well as problems with a number of modified Cds have been well documented (Frank et al, 1976;Irie et al, 1992;Davis & Brewster, 2004;Zhao et al, 2010). The toxicological effects of Cds are primarily due to to inclusion complexation with cholesterol and membrane lipids (Stella & He, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Cyclodextrin modulates the cytotoxic effects of chlorhexidine on microrganisms and cellsin vitro

et al. 2014

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cyclodextrin modulates the cytotoxic effects of chlorhexidine on microrganisms and cellsin vitro

et al. 2014

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“…Cyclodextrins are cyclic oligomers of glucose that have the capacity to sequester lipophiles in their hydrophobic core (Pitha et al, 1988). The water-soluble M␤CD is known to form soluble inclusion complexes with cholesterol, thereby enhancing its solubility in aqueous solution (Pitha et al, 1988;Irie et al, 1992). In this article we demonstrate that cholesterol plays an important role in the invagination of clathrin-coated pits and therefore in clathrin-dependent endocytosis.…”

Section: Introductionmentioning

confidence: 83%

Extraction of Cholesterol with Methyl-β-Cyclodextrin Perturbs Formation of Clathrin-coated Endocytic Vesicles

Rodal

Skretting

Garred

et al. 1999

MBoC

932

776

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The importance of cholesterol for endocytosis has been investigated in HEp-2 and other cell lines by using methyl-␤-cyclodextrin (M␤CD) to selectively extract cholesterol from the plasma membrane. M␤CD treatment strongly inhibited endocytosis of transferrin and EGF, whereas endocytosis of ricin was less affected. The inhibition of transferrin endocytosis was completely reversible. On removal of M␤CD it was restored by continued incubation of the cells even in serum-free medium. The recovery in serum-free medium was inhibited by addition of lovastatin, which prevents cholesterol synthesis, but endocytosis recovered when a water-soluble form of cholesterol was added together with lovastatin. Electron microscopical studies of M␤CD-treated HEp-2 cells revealed that typical invaginated caveolae were no longer present. Moreover, the invagination of clathrin-coated pits was strongly inhibited, resulting in accumulation of shallow coated pits. Quantitative immunogold labeling showed that transferrin receptors were concentrated in coated pits to the same degree (approximately sevenfold) after M␤CD treatment as in control cells. Our results therefore indicate that although clathrin-independent (and caveolae-independent) endocytosis still operates after removal of cholesterol, cholesterol is essential for the formation of clathrin-coated endocytic vesicles.

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“…Note that in the absence of LUVs, the equilibration of label in these studies is dependent on the amount of UC mass present in the media (initially in HDL) relative to that present in the cells. The final approach to demonstrate shuttling was to use an artificial acceptor of cholesterol, cyclodextrins, 35,[37][38][39][40] that our preliminary studies showed to be unable to acquire PL from LUVs (data not shown). Hence, remodeling of the small acceptor does not occur when a mixture of cyclodextrin and LUVs is used to remove cellular cholesterol.…”

Section: Shuttling Of Uc From Cells To the Luv Sinkmentioning

confidence: 99%

Remodeling and Shuttling

Rodrigueza

Williams

Rothblat

et al. 1997

ATVB

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In normal physiology, cells are exposed to cholesterol acceptors of different sizes simultaneously. The current study examined the possible interactions between two different classes of acceptors, one large (large unilamellar phospholipid vesicles, LUVs) and one small (HDL or other small acceptors), added separately or in combination to Fu5AH rat hepatoma cells. During a 24-hour incubation, LUVs of palmitoyl-oleoyl phosphatidylcholine at 1 mg phospholipid (PL) per milliliter extracted ≈20% of cellular unesterified cholesterol (UC) label and mass in a slow, continuous fashion (half-time [t½] for UC efflux was ≈50 hours) and human HDL 3 at 25 μg PL per milliliter extracted ≈15% cellular UC label with no change in cellular cholesterol mass (t½ of ≈8 hours). In contrast, the combination of LUVs and HDL 3 extracted over 90% of UC label (t½ of ≈4 hours) and ≈50% of the UC mass, indicating synergy. To explain this synergy, specific particle interactions were examined, namely, remodeling, in which the two acceptors alter each other's composition and thus the ability to mobilize cellular cholesterol, and shuttling, in which the small acceptor ferries cholesterol from cells to the large acceptor. To examine remodeling, LUVs and HDL were coincubated and reisolated before application to cells. This HDL became UC depleted, PL enriched, and lost a small amount of apolipoprotein A-I. Compared with equivalent numbers of control HDL particles, remodeled HDL caused faster efflux (t½ ≈4 hours) and exhibited a greater capacity to sequester cellular cholesterol over 24 hours (≈38% versus ≈15% for control HDL), consistent with their enrichment in PL. Remodeled LUVs still extracted ≈20% of cellular UC. Thus, remodeling accounted for some but not all of the synergy between LUVs and HDL. To examine shuttling, several approaches were used. First, reisolation of particles after an 8-hour exposure to cells revealed that HDL contained very little of the cellular UC label. The label was found almost entirely with the LUVs, suggesting that LUVs continuously stripped the HDL of cellular UC. Second, bidirectional flux studies demonstrated that LUVs blocked the influx of HDL UC label into cells, while the rate of efflux of cellular UC was maintained. These kinetic effects explained the massive net loss of cellular UC to LUVs with HDL. Third, cyclodextrin, an artificial small acceptor that does not acquire PL and hence does not become remodeled, exhibitedCorrespondence to Dr Michael C. Phillips, Department of Biochemistry, Medical College of Pennsylvania and Hahnemann University, 2900 Queen Ln, Philadelphia, PA 19129. Portions of this work were published in abstract form in Abstracts Submitted to the Council on Arteriosclerosis for the 68th Scientific Sesssions of the American Heart Association. 1995:54. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript substantial synergy with LUVs, supporting shuttling. Thus, the presence of large and small acceptors together can overcome intrinsic deficiencies in...

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Hydroxypropylcyclodextrins in Parenteral use. I: Lipid Dissolution and Effects on Lipid Transfers in Vitro

Cited by 131 publications

References 1 publication

Cyclodextrin modulates the cytotoxic effects of chlorhexidine on microrganisms and cellsin vitro

Cyclodextrin modulates the cytotoxic effects of chlorhexidine on microrganisms and cellsin vitro

Extraction of Cholesterol with Methyl-β-Cyclodextrin Perturbs Formation of Clathrin-coated Endocytic Vesicles

Remodeling and Shuttling

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