Liposome-water Partition Coefficients Research Articles

Synergistic Effects of IMX-104 Components in Membrane Absorption: A Computational Study.

New insensitive munitions such as IMX-104 formulations are being developed to improve the safety suffering from accidental stimulations. Experimental data indicated the synergistic toxicity of 2,4-dinitroanisole (DNAN) and hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in IMX-104, which increased the concern about its environmental and health threats. Indeed, little is known about the synergistic mechanism. Here, we investigated the membrane absorption of DNAN and RDX as the first step toward uncovering synergistic toxicity. The permeability coefficient, transmembrane time, and liposome-water partition coefficient were calculated by the umbrella sampling technique. The results show that component RDX in the IMX-104 formulation promotes the membrane absorption of another more toxic component DNAN, suggesting that the synergistic toxicity effect of IMX-104 may emerge from their membrane adsorption stage. In detail, the integrating free-energy curves show that DNAN, RDX, or their mixture in membranes would promote subsequent molecules passing through membranes. For the mixture of DNAN and RDX, RDX was absorbed by the membrane before DNAN. Postabsorbed DNAN tends to stay around RDX, which is due to the strong van der Waals (VDW) interaction between them. RDX stabilized under phospholipid headgroups limits the overflow of DNAN from the membrane, which results in 11% more absorption of DNAN by the membrane than in the case of the pure DNAN system.

Study of Resveratrol's Interaction with Planar Lipid Models: Insights into Its Location in Lipid Bilayers.

Resveratrol, a polyphenolic molecule found in edible fruits and vegetables, shows a wide range of beneficial effects on human health, including anti-microbial, anti-inflammatory, anti-cancer, and anti-aging properties. Due to its poor water solubility and high liposome-water partition coefficient, the biomembrane seems to be the main target of resveratrol, although the mode of interaction with membrane lipids and its location within the cell membrane are still unclear. In this study, using electrophysiological measurements, we study the interaction of resveratrol with planar lipid membranes (PLMs) of different composition. We found that resveratrol incorporates into palmitoyl-oleoyl-phosphatidylcholine (POPC) and POPC:Ch PLMs and forms conductive units unlike those found in dioleoyl-phosphatidylserine (DOPS):dioleoyl-phosphatidylethanolamine (DOPE) PLMs. The variation of the biophysical parameters of PLMs in the presence of resveratrol provides information on its location within a lipid double layer, thus contributing to an understanding of its mechanism of action.

A relationship between membrane permeation and partitioning of nitroaromatic explosives and their functional groups. A computational study.

Nitroaromatic explosives, such as 2,4,6-trinitrotoluene, are representative aromatic compounds, which are generally highly toxic. For their toxic mechanisms, little is known about their interaction with cell membranes, although this is essential for their absorption, distribution, metabolism, excretion and toxicity profiling. Here, we investigated the membrane permeation and partitioning of 12 nitroaromatic explosives with typical functional groups (e.g., -NO2, -NH2, -OCH3 and -OH) by all-atom molecular dynamics simulations. Based on free-energy curves, we obtained three key parameters that describe the behavior of permeation and partitioning, namely liposome-water partition coefficient (KLW), permeability coefficient (P) and translocation time (τ). Functional groups contribute little to KLW, indicating that the membrane absorption of nitroaromatic explosives is primarily controlled by the hydrophobic effect of the benzene ring. P shows an obvious decline with increasing polar group number (Np), and therefore τ exhibits a continuous increase. In addition, the preferred location (zmin) of explosive molecules in membranes is closer to the head group of lipids when they have more polar groups. Further analysis shows that the hydrogen bond (H-bond) interaction of explosives with water and lipids plays a crucial role in the dependence of permeation and partitioning on polar groups. The molecules with larger Np can form more H-bonds with water in the aqueous phase, which limits their motion into the deeper hydrophobic region of membranes. Moreover, the desolvation/loss of H-bonds leave zmin controls the membrane permeation properties, which is also correlated with Np. The work reveals the physical essence of the relationship between the membrane permeation and partitioning of nitroaromatic explosives and their functional groups. These results may be also applicable to other (e.g., polycyclic) nitroaromatic compounds.

Molecular Simulation Studies on the Interactions of 2,4,6-Trinitrotoluene and Its Metabolites with Lipid Membranes.

The penetration of chemicals into biological membranes is a key factor in the determination of their possible effects on organisms; this complex process involves mainly the interaction between chemicals and membranes. Here, we reported the interaction between a highly toxic class of explosives [2,4,6-trinitrotoluene (TNT) and its metabolites] and lipid membranes using molecular dynamics simulations. We calculated the permeability coefficient, transmembrane time, and liposome-water partition coefficient by integrating free-energy curves for all species. The results showed that TNT had a lower transmembrane capacity than its metabolites. Based on the liposome-water partition coefficient, we demonstrated that the membrane affinity of TNT is larger than that of its diamino metabolites but less than that of its monoamino metabolites. This result can qualitatively explain the difference of bioconcentration factors in experiments. The accumulation of TNT and metabolites in membranes can change the membrane structure, such as the area per lipid, the thickness of lipid bilayers, and the order of lipid tails and, further, the penetration of water. All of these are closely related to the interactions (mainly hydrogen bonds) of TNT and metabolites with lipid and water molecules. This work has a certain significance for understanding the toxicity of TNT and its metabolites.

QSAR for baseline toxicity and classification of specific modes of action of ionizable organic chemicals in the zebrafish embryo toxicity test

The fish embryo toxicity (FET) test with the zebrafish Danio rerio is widely used to assess the acute toxicity of chemicals thereby serving as animal alternative to the acute fish toxicity test. The minimal toxicity of neutral chemicals in the FET can be predicted with a previously published Quantitative Structure-Activity Relationship (QSAR) based on the liposome-water partition coefficient Klipw. Such a QSAR may serve to plan toxicity testing and to evaluate whether an observed effect is caused by a specific mode of action (MoA). The applicability domain of this QSAR was extended to ionizable organic chemicals (IOC) without any modification of slope and intercept simply by replacing the Klipw with the speciation-corrected liposome-water distribution ratio (Dlipw(pH)) as descriptor for the uptake into the embryo. FET LC50 values of IOCs were extracted from an existing FET database and published literature. IOCs were selected that are present concomitantly as neutral and charged, species, i.e., acids with an acidity constant pKa <10 and bases with pKa>5. IOCs were grouped according to their putative MoA of acute aquatic toxicity. The toxic ratios (TR) in the FET were derived by of the experimental FET-LC50 in comparison with the baseline toxicity QSAR. Baseline toxicants were confirmed to align well with the FET baseline toxicity QSAR (TR < 10). Chemicals identified to act as specific or reactive chemicals with the toxic ratio analysis in the FET test (TR > 10) were generally consistent with MoA classification for acute fish toxicity with a few exceptions that were suspected to have had issues with the stability of the pH during testing. One critical aspect for the effect analysis of ionizable chemicals is the pH, since the difference between pH and pKa determines the speciation and thereby the Dlipw(pH).

Evaluation of the ability of arsenic species to traverse cell membranes by simple diffusion using octanol–water and liposome–water partition coefficients

Arsenic metabolism in living organisms is dependent on the ability of different arsenic species to traverse biological membranes. Simple diffusion provides an alternative influx and efflux route to mediated transport mechanisms that can increase the amount of arsenic available for metabolism in cells. Using octanol–water and liposome–water partition coefficients, the ability of arsenous acid, arsenate, methylarsonate, dimethylarsinate, thio-methylarsonate, thio-dimethylarsinic acid, arsenotriglutathione and monomethylarsonic diglutathione to diffuse through the lipid bilayer of cell membranes was investigated. Molecular modelling of arsenic species was used to explain the results. All arsenic species with the exception of arsenate, methylarsonate and thio-methylarsonate were able to diffuse through the lipid bilayer of liposomes, with liposome–water partition coefficients between 0.04 and 0.13. Trivalent arsenic species and thio-pentavalent arsenic species showed higher partition coefficients, suggesting that they can easily traverse cell membranes by passive simple diffusion. Given the higher toxicity of these species compared to oxo-pentavalent arsenic species, this study provides evidence supporting the risk associated with human exposure to trivalent and thio-arsenic species.

Development of a general baseline toxicity QSAR model for the fish embryo acute toxicity test

Fish embryos have become a popular model in ecotoxicology and toxicology. The fish embryo acute toxicity test (FET) with the zebrafish embryo was recently adopted by the OECD as technical guideline TG 236 and a large database of concentrations causing 50% lethality (LC50) is available in the literature. Quantitative Structure-Activity Relationships (QSARs) of baseline toxicity (also called narcosis) are helpful to estimate the minimum toxicity of chemicals to be tested and to identify excess toxicity in existing data sets. Here, we analyzed an existing fish embryo toxicity database and established a QSAR for fish embryo LC50 using chemicals that were independently classified to act according to the non-specific mode of action of baseline toxicity. The octanol-water partition coefficient Kow is commonly applied to discriminate between non-polar and polar narcotics. Replacing the Kow by the liposome-water partition coefficient Klipw yielded a common QSAR for polar and non-polar baseline toxicants. This developed baseline toxicity QSAR was applied to compare the final mode of action (MOA) assignment of 132 chemicals. Further, we included the analysis of internal lethal concentration (ILC50) and chemical activity (La50) as complementary approaches to evaluate the robustness of the FET baseline toxicity. The analysis of the FET dataset revealed that specifically acting and reactive chemicals converged towards the baseline toxicity QSAR with increasing hydrophobicity. The developed FET baseline toxicity QSAR can be used to identify specifically acting or reactive compounds by determination of the toxic ratio and in combination with appropriate endpoints to infer the MOA for chemicals.

Native Oxy-PAHs, N-PACs, and PAHs in Historically Contaminated Soils from Sweden, Belgium, and France: Their Soil-Porewater Partitioning Behavior, Bioaccumulation in Enchytraeus crypticus, and Bioavailability

Soil quality standards are based on partitioning and toxicity data for laboratory-spiked reference soils, instead of real world, historically contaminated soils, which would be more representative. Here 21 diverse historically contaminated soils from Sweden, Belgium, and France were obtained, and the soil-porewater partitioning along with the bioaccumulation in exposed worms (Enchytraeus crypticus) of native polycyclic aromatic compounds (PACs) were quantified. The native PACs investigated were polycyclic aromatic hydrocarbons (PAHs) and, for the first time to be included in such a study, oxygenated-PAHs (oxy-PAHs) and nitrogen containing heterocyclic PACs (N-PACs). The passive sampler polyoxymethylene (POM) was used to measure the equilibrium freely dissolved porewater concentration, Cpw, of all PACs. The obtained organic carbon normalized partitioning coefficients, KTOC, show that sorption of these native PACs is much stronger than observed in laboratory-spiked soils (typically by factors 10 to 100), which has been reported previously for PAHs but here for the first time for oxy-PAHs and N-PACs. A recently developed KTOC model for historically contaminated sediments predicted the 597 unique, native KTOC values in this study within a factor 30 for 100% of the data and a factor 3 for 58% of the data, without calibration. This model assumes that TOC in pyrogenic-impacted areas sorbs similarly to coal tar, rather than octanol as typically assumed. Black carbon (BC) inclusive partitioning models exhibited substantially poorer performance. Regarding bioaccumulation, Cpw combined with liposome-water partition coefficients corresponded better with measured worm lipid concentrations, Clipid (within a factor 10 for 85% of all PACs and soils), than Cpw combined with octanol-water partition coefficients (within a factor 10 for 76% of all PACs and soils). E. crypticus mortality and reproducibility were also quantified. No enhanced mortality was observed in the 21 historically contaminated soils despite expectations from PAH spiked reference soils. Worm reproducibility weakly correlated to Clipid of PACs, though the contributing influence of metal concentrations and soil texture could not be taken into account. The good agreement of POM-derived Cpw with independent soil and lipid partitioning models further supports that soil risk assessments would improve by accounting for bioavailability. Strategies for including bioavailability in soil risk assessment are presented.

Synthesis, Characterization, and Liposome Partition of a Novel Tetracycline Derivative Using the Ionic Liquids Framework

Recently, efforts have been put on the development of new drug formulations using ionic liquid framework. In this work, two different species of abroad-spectrum polyketide antibiotic, tetracycline, are studied in terms of some important properties for antibiotics such as solubility in water and hydrophilic-hydrophobic balance. Tetracycline was used as cation, whereas docusate, a biocompatible anion, which enables the tailoring of the hydrophilicity of salts, was chosen as the anion. The developed innovative ion pair, tetracycline docusate, was characterized in terms of its thermal stability, water solubility, octanol-water, and liposome-water partition coefficients, using UV-vis spectrophotometry because of the absorbance of tetracycline around 270 nm. Egg yolk phosphatidylcholine liposomes were used as cell membrane models, and the interactions of both tetracycline hydrochloride and tetracycline docusate with the liposomes were quantified by determination of the partition coefficient using derivative spectrophotometry. A theoretical model based on simple partition drugs between two different media was used to determine the partition coefficient in liposomes.

Evaluation of Liposome−Water Partitioning for Predicting Bioaccumulation Potential of Hydrophobic Organic Chemicals

Considering the importance of bioaccumulation factors (BAFs) in risk assessment of chemicals and the ethical issues and complexity of the determination of these factors in standard tests with living organisms, there is a need for alternative approaches for predicting bioaccumulation. In this study, liposome-water partitioning coefficients as determined by using solid-phase microextraction (SPME) were evaluated for the cause of assessing bioaccumulation potential of hydrophobic organic chemicals (HOCs). To this end, the SPME method was mapped (in terms of mass balance, mode of spiking, kinetics, and reproducibility) and validated against literature data. Furthermore, the robustness of liposomes as partitioning phase was investigated (in terms of chemical loading, and pH and ionic strength of the medium), and finally liposome-water partition coefficients (K(lipw)) determined for polycyclic aromatic hydrocarbons (PAHs; 4.5 < logK(ow) < 7.2) were compared with literature BAF values for several aquatic species. The results indicated that (i) SPME is a valid, fast, and reproducible method for measuring K(lipw) values; (ii) liposomes provide a very robust partitioning phase; and (iii) K(lipw) values agreed very well with literature PAH BAF values. SPME-derived K(lipw) values therefore seem a very promising predictor of bioaccumulation potential of HOCs. By including model- or in vitro-derived biotransformation rates, bioaccumulation potential estimates might be converted into surrogate BAFs, thereby extending the applicability of K(lipw) values to metabolizable chemicals and species with more advanced biotransformation capacity.

Physiological Modes of Action of Fluoxetine and its Human Metabolites in Algae

Fluoxetine, the active ingredient of many antidepressants, was identified as specifically toxic toward algae in a quantitative structure-activity relationship (QSAR) analysis with literature data for algae, daphnia, and fish. The goal of this study was to elucidate the mode of action in algae and to evaluate the toxicity of the major human metabolites of fluoxetine using two different algae tests. The time dependence and sensitivity of thedifferenteffectendpointsyield information on the physiological mode of action. Baseline toxicity was predicted with QSARs based on measured liposome-water partition coefficients. The ratio of predicted baseline toxicity to experimental toxicity (toxic ratio TR) gives information on the intrinsic potency (extent of specificity of effect). The metabolite p-trifluoromethylphenol was classified to act as baseline toxicant Fluoxetine (TR 60-150) and its pharmacologically active metabolite norfluoxetine (TR 10-80) exhibited specific toxicity. By comparison with reference compounds we conclude that fluoxetine and norfluoxetine have an effect on the energy budget of algal cells since the time pattern of these two compounds is most similar to that observed for norflurazon, but they act less specifically as indicated by lower TR values and the similarity of the effect pattern to baseline toxicants. The mixture toxicity of fluoxetine and its human metabolites norfluoxetine and p-TFMP can be predicted using the model of concentration addition for practical purposes of risk assessment despite small deviations from this model for the specific endpoints like PSII inhibition because the integrative endpoints like growth rate and reproduction in all cases gave agreement with the predictions for concentration addition.

Studying the interactions of drugs and hydrophobic model membranes using contact angle goniometry

This study demonstrates a method where contact angle goniometry combined with surface tension measurements is used to assess the interactions of drugs with the hydrophobic core of a biological membrane. To this end, self-assembled monolayers (SAMs) of two alkanethiol and one thiolipid on Au(1 1 1) surfaces are used as model membranes and their interaction with six β-blockers is studied. The Gibbs equation and the Langmuir adsorption isotherm are used to determine the partition coefficients for the adsorption of the drugs, which are compared to the octanol–water partition coefficients as well as the liposome–water partition coefficients. The ability of the different SAMs to serve as model membranes in partitioning of drugs is discussed.

Evaluation of Ferulic Acid-Biomembrane Interaction by Liposome Electrokinetic Chromatography

A facile method for evaluating acidic drug-biomembrane interaction was established by liposome electrokinetic chromatography (LEKC). LEKC is a capillary electrophoresis technique, where liposome is incorporated into a buffer solution and acts as a pseudostationary phase using the structural similarity of liposome and biomembrane. Liposome–water partition coefficient ( K lw) of ferulic acid was determined within a few minutes. The effect of cholesterol content, buffer pH, and buffer composition on K lw was investigated, respectively. An increase in cholesterol content (0–30%) and pH values (4.00–12.00) resulted in a lower K lw . In different buffer systems, the greater the ionic strength, the larger K lw was. The difference of K lw revealed ferulic acid–biomembrane interaction.

Potentiometric determination of octanol–water and liposome–water partition coefficients (logP) of ionizable organic compounds

Abstract The logarithm of the octanol–water partition coefficient, log P, is a key physicochemical property for both pharmaceutical drugs and agrochemicals. It is also required by legislation as part of the physicochemical properties profile for high volume production chemicals. This Letter describes a simple method for determining log P values (over a wide range from −0.8 to 5.3) for 12 organic weak acids and bases using potentiometric titrations, with octanol or phosphatidyl choline liposomes as the partitioning medium. Such titrations take comparatively little time (about 30–45 min per titration), are easy to implement, and can be carried out with an inexpensive laboratory titrator.

Characterization of solvation properties of lipid bilayer membranes in liposome electrokinetic chromatography

The nature of solute interactions with biomembrane-like liposomes, made of naturally occurring phospholipids and cholesterol, was characterized using electrokinetic chromatography (EKC). Liposomes were used as a pseudo-stationary phase in EKC that provided sites of interactions for uncharged solutes. The retention factors of uncharged solutes in liposome EKC are directly proportional to their liposome–water partition coefficients. Linear solvation energy relationship (LSER) models were developed to unravel the contributions from various types of interactions for solute partitioning into liposomes. Size and hydrogen bond acceptor strength of solutes are the main factors that determine partitioning into lipid bilayers. This falls within the general behavior of solute partitioning from an aqueous into organic phases such as octanol and micelles. However, there exist subtle differences in the solvation properties of liposomes as compared to those of octanol and various micellar pseudo-phases such as aggregates of sodium dodecyl sulfate (SDS), sodium cholate (SC), and tetradecylammonium bromide (TTAB). Among these phases, the SDS micelles are the least similar to the liposomes, while octanol, SC, and TTAB micelles exhibit closer solvation properties. Subsequently, higher correlations are observed between partitioning into liposomes and the latter three phases than that into SDS.

Rapid determination of liposome–water partition coefficients (Klw) using liposome electrokinetic chromatography (LEKC)

Liposome Electrokinetic Chromatography (LEKC) provides a simple and facile approach for determining liposome-water partition coefficients, Klw. LEKC is a Capillary Electrophoresis (CE) technique where liposomes are incorporated into a buffer solution and act as a pseudostationary phase providing sites of interaction for solutes. The retention factors of solutes in LEKC are directly proportional to Klw. This article describes how LEKC can be used to determine Klw for both neutral and charged solutes. The Klw values for a group of neutral aromatic compounds, beta-blockers, and other drugs are reported. In addition, the usefulness of two quantitative structure partition relationships (QSPR) for estimation of Klw is demonstrated. One is the logarithmic linear relationship between liposome water and octanol-water partition coefficients (Pow). The other is the Linear Solvation Energy Relationship (LSER). The calculated Klw values from the two QSPR agree nicely with the observed values and with one another.

A comparison of solution properties of cholesterol and 25-hydroxycholesterol

Although 25-hydroxycholesterol is a potent effector of mammalian cellular cholesterol biosynthesis, cholesterol itself is not. In an effort to explain this difference, the critical micellar concentration, liposome-water partition coefficient, and capacity for acyl chain ordering of 25-hydroxycholesterol are measured and compared to those of cholesterol. It is found that 25-hydroxycholesterol differs from cholesterol by existing in monomeric form in aqueous solution at physiologically active concentrations. It is suggested that this property allows 25-hydroxycholesterol but not cholesterol itself to interact in a concentration-dependent fashion with particular proteins.