Interaction with membrane lipids

It has been generally accepted that anesthetics interact with membrane lipids as a primary step of anesthesia. The detailed mechanism of the anesthetic action is, however, still controversial. This is mainly due to the absence of specific information on delivery sites in membranes. The NMR data for the delivery site of drugs in membranes are of great use. 

Before the first indication of the existence of cannabinoid receptors, the prevailing theory on the mechanism of cannabinoid activity was that cannabinoids exert their effects by nonspecific interactions with cell membrane lipids (Makriyannis, 1990). Such interactions can increase the membrane fluidity, perturb the lipid bilayer and concomitantly alter the function of membrane-associated proteins (Loh, 1980). A plethora of experimental evidence suggests that cannabinoids interact with membrane lipids and modify the properties of membranes. However, the relevance of these phenomena to biological activities is still only, at best, correlative. An important conundrum associated with the membrane theories of cannabinoid activity is uncertainty over whether cannabinoids can achieve in vivo membrane concentrations comparable to the relatively high concentrations used in in vitro biophysical studies (Makriyannis, 1995). It may be possible that local high concentrations are attainable under certain physiological circumstances, and, if so, some of the cannabinoid activities may indeed be mediated through membrane perturbation. 

Fullerene showed antibacterial activity, which can be attributed to different interactions of C60 with biomolecules (Da Ros et al., 1996). In fact, there is a possibility to induce cell membrane disruption. The fullerene sphere seems not really adaptable to planar cellular surface, but for sure the hydrophobic surface can easily interact with membrane lipids and intercalate into them. However, it has been demonstrated that fullerene derivatives can inhibit bacterial growth by unpairing the respiratory chain. There is, first, a decrease of oxygen uptake at low fullerene derivative concentration, and then an increase of oxygen uptake, which is followed by an enhancement of hydrogen peroxide production. The higher concentration of C60 seems to produce an electron leak from the bacterial respiratory chain (Mashino et al., 2003). 

Flavonoids bear different degrees of hydroxylation, polymerization, and methylation that define both specific and nonspecific interactions with membrane lipids. Molecule size, tridimensional structure, and hydrophili-city/hydrophobicity are chemical parameters that determine the nature and extent of flavonoid interactions with lipid bilayers. The hydrophilic character of certain flavonoids and their oligomers endows these molecules with the ability to bind to the polar headgroups of lipids localized at the water-lipid interface of membranes. On the other hand, flavonoids with hydrophobic character can reach and cross the lipid bilayer. In this section, we will discuss current experimental evidences on the consequences of flavonoid interactions with both the surface and the hydrophobic core of the lipid bilayer. 

Cationic PCs of high and low-transfection can be discriminated only on the basis of their interactions with membrane lipids. There appears to exist no correlation between lipoplex phase behavior and transfection activity. However, there is a distinct, well-expressed correlation between transfection activity and the way... 

At high concentrations, phenytoin also inhibits the release of serotonin and norepinephrine, promotes the uptake of dopamine, and inhibits monoamine oxidase activity. The drug interacts with membrane lipids this binding might promote the stabilization of the membrane. In addition, phenytoin paradoxically causes excitation in some cerebral neurons. A reduction of calcium permeability, with inhibition of calcium influx across the cell membrane, may explain the ability of phenytoin to inhibit a variety of calcium-induced secretory processes, including release of hormones and neurotransmitters. The significance of these biochemical actions and their relationship to phenytoin s clinical activity are unclear. 

Sharom FJ. The P-glycoprotein multi drug transporter interactions with membrane lipids, and their modulation of activity. Biochem Soc Trans 1997 25(3) 1088-1096. 

Amphotericin B is highly lipophilic (Figure 29.14) and interacts with membrane lipid sterols, such as cholesterol, to disrupt membrane permeability. Because amphotericin is freely filtered, it achieves high concentrations in distal tubular fluid and easily forms complexes with cholesterol and other lipids present in distal tubular luminal membranes. Amphotericin effectively transforms the tight distal tubular epithelium into an epithelium leaky to water, H+ and K+. Functional abnormalities observed with amphotericin B are attenuated when the antifungal agent is administered as an emulsion formulation whereby amphotericin is incorporated into lipid... 

Furthermore, the expression and function of the Pgp can be modulated by indirect mechanisms, such as interactions with membrane lipids [67] or inhibition of protein kinase C. The reversal of MDR is established using tumor cells lines that are made resistant by the exposure to an anticancer agent or by transfection of the mdrl or mrpl genes. The parameter most widely used to show the activity of MDR reversal agents is reversal factor (RF). This type of assay assumes that the reversal agent does not show inherent cytotoxicity at the concentrations tested. 

Sphingomyelinases and Their Interaction with Membrane Lipids... 

The mechanism of peptide transport into the cell is still uncertain. Peptides derived from Antp-HD appear to be internalized by a receptor-independent mechanism that depends on direct interaction with membrane lipids peptide association with lipids and internalization via an inverted micelle that crosses the membrane, has been suggested [65]. In the case of transportan (Table 8.8), binding to the cell surface and internalization occur quickly (in 1 min with maximum concentration at 20 min) and efficiently (10-16% uptake) [63]. As in Antp-HD, uptake does not appear to require specific receptors, as internalization is not saturable. Once in the cell, most of the peptide is associated with membranes, including the nuclear membrane. Similar observations have been reported in Tat peptide sequence derived from HIV-1 [62]. 

We therefore have investigated the molecular order and dynamics of model membranes consisting of different thylakoid lipids. -Carotene and Q-tocopherol both absorb light while a-tocopherol is also fluorescent. These properties are particular suitable for studies of their interactions with membrane lipids using polarized light. In this way both compounds act as probe molecules reporting on their interaction with their environment. 

Photosystem II reaction center is susceptible to light induced damage and steady state photosynthesis is maintained by continual repair of the photo-inactivated photosystems. An increase in the rate of inactivation (by over excitation of PS II) or a decrease in the rate of repair of PSII centers can result in accumulation of damaged PS II and consequent photoinhibition of photosynthesis. Since the assembly and stability of PS II complex involves close interaction with membrane lipids, photoinhibition and recovery of PS II centers are likely to be affected by the lipid composition of the thylakoid membrane. 

---