Lipophilic environment

A close relationship exists between physicochemical properties of pigment molecules and their ability to be absorbed and thus to exhibit biological functions. Carotenoids are hydrophobic molecules that require a lipophilic environment. In vivo, they are found in precise locations and orientations within biological membranes. For example, the dihydroxycarotenoids such as lutein and zeaxanthin orient themselves perpendicularly to the membrane surface as molecular rivets in order to expose their hydroxyl groups to a more polar environment. 

In contrast, the carotenes such as p-carotene and lycopene may position themselves parallel to the membrane surfaces to remain in a more lipophilic environment in the inner cores of the bilayer membranes. To move through an aqueous environment, carotenoids can be incorporated into lipid particles such as mixed micelles in the gut lumen or lipoproteins in the blood circulation and they can also form complexes with proteins with unspecific or specific bindings. 

Lipophilicity represents the affinity of a molecule or a moiety for a lipophilic environment. It is commonly measured by its distribution behavior in a biphasic system, either liquid-liquid (e.g. partition coefficient in 1-octanol-water) or solid-liquid (retention on reversed-phase high-performance liquid chromatography or thin-layer chromatography system). 

Lipophilicity is a molecular property expressing the relative affinity of solutes for an aqueous phase and an organic, water-immiscible solvent. As such, lipophilicity encodes most of the intermolecular forces that can take place between a solute and a solvent, and represents the affinity of a molecule for a lipophilic environment. This parameter is commonly measured by its distribution behavior in a biphasic system, described by the partition coefficient of the species X, P. Thermodynamically, is defined as a constant relating the activity of a solute in two immiscible phases at equilibrium [111,112]. By convention, P is given with the organic phase as numerator, so that a positive value for log P reflects a preference for the lipid phase ... 

Carotenoids are hydrophobic molecules and thus are located in lipophilic sites of cells, such as bilayer membranes. Their hydrophobic character is decreased with an increased number of polar substitutents (mainly hydroxyl groups free or esterified with glycosides), thus affecting the positioning of the carotenoid molecule in biological membranes. For example, the dihydroxycarotenoids such as LUT and zeaxanthin (ZEA) may orient themselves perpendicular to the membrane surface as molecular rivet in order to expose their hydroxyl groups to a more polar environment. In contrast, the carotenes such as (3-C and LYC could position themselves parallel to the membrane surface to remain in a more lipophilic environment in the inner core of the bilayer membranes (Parker, 1989 Britton, 1995). Thus, carotenoid molecules can have substantial effects on the thickness, strength, and fluidity of membranes and thus affect many of their functions. 

Therefore, at least in vitro, the protective effects of flavonoids against LDL against oxidation depend on their structural properties in terms of the response of the particular flavonoid to copper and iron ions, whether chelation or oxidation, their partitioning abilities between the aqueous compartment and the lipophilic environment within the LDL particle, their hydrogen-donating antioxidant properties and their capacity to reduce the formation or release of flee radicals by the cells (probably related to the inhibition of NAD(P)H-oxidoreductase and/or PKC activity). 

For proteins with multiple transmembrane domains, it is not necessary to have exclusively hydrophobic amino acids a pair of amino acids with opposite charges may be present in the lipophilic environment of the membrane. Therefore a search for amphipathic a-helices must be undertaken. Amphipathic helices have well-defined hydrophobic character, the hydrophobic face which would project towards the membrane/lipid environment, and a hydrophilic face, which would project out into the aqueous phase or towards the core of a helix bundle. Often times the distinction is not clear and there are regions of mixed hydrophobic/hydrophilic character. Graphically this can be realized with a helical-wheel representation in which the amino acid side chains project out, at 100 degree intervals, from the view along the long, helical axis. 

Figure 2 Role of water molecules in hydrogen bonds (upper part) and lipophilic interactions (lower part). In the unbound state (left side), the polar groups of the ligand and the protein form hydrogen bonds to water molecules. These water molecules are replaced upon complex formation. The hydrogen-bond inventory (total number of hydrogen bonds) does not change. In contrast, the formation of lipophilic contact increases the total number of hydrogen bonds due to the release of water molecules from the unfavorable lipophilic environment.

The lipophilic environment created by residues that form the adenine-binding pocket extends sufficiently beyond the opening of the pocket to create an additional lipophilic binding area in front of the adenine. This pocket may not be accessible to inhibitors that bind into tightly closed adenine pockets. Inhibitor accessibility to this pocket may also be restricted for some kinase families. For example, the AGC family kinases (PKA, PKC, AKT) have a C-terminal tail that extends back into N-terminal domain and caps the adenine site with a phenylalanine (see Section 2.2.3.3). Inhibitor-kinase structures that bind an aryl ring in this site include 10 in CDK2 (Fig. 2.5 B) [67], 9 in CDK2 [66], and 17 (Scheme 2.4) in p38... 

However, after a short time, the drug leaves the brain again and accumulates in the lean tissues (such as muscle), from where it finally redistributes to the body fat. This reflects that the fat provides the most favourable (lipophilic) environment however, since it is only weakly perfused, substance exchange works more slowly than with the other tissues. Note that, in this particular case, drug action is not terminated by elimination of the drug (as is usually the case), but solely by its redistribution from the site of action (the brain) to inert reservoirs (muscle / fat). Ultimate elimination is very slow - it takes days to complete - and involves hepatic metabolism of the drug, followed by urinary excretion. 

The second property of importance for bioavailability is the polar surface area (PSA) that is associated with intestinal absorption and cell membrane penetration by passive transport. Compounds with a high polar surface are less likely to penetrate the lipophilic environment of the cell membranes by passive transport. Like the logP, PSA can be computed by summing up fragment contributions (8) with H-bonding fragments as the main contributor. 

Bile salts act as "detergents" in nature to maintain insoluble (fat-soluble) compounds in water solution. The bile salts form mixed micelles that consist of amphipathic bile salt molecules surrounding the lipophilic (fal-soJublc) molecules. The hydrophilic ends of the amphipathic molecules face outward, forming a lipophilic environment in the interior of the micelle. Bile salt molecules contain acid groups, such as carboxyl and sulfonyl groups, that usually are ionized under physiological conditions. 

A hydrophobic IL, 1-butyl-3-decylimidazolium hexafluoroantimonate [dbim][SbF6], was then chosen for particle impregnation, thus creating a lipophilic environment around the particle where reactions can take place. Thus, 42 is added to a solution of dbim SblvJ in ethyl acetate to give, after solvent removal under reduced pressure, a fine powder of SiO2-Sc-IL (43). 

While comeocytes can be considered to be hydrophilic domains, they are surrounded by a lipid-rich matrix mainly comprising ceramides, free fatty acids and cholesterol (Downing et al, 1987). Thus, the intercellular domain is predominantly a lipophilic environment. This combination imparts a degree of amphiphobicity upon... 

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