Chemical Lipophilicity Research Articles

Novel and legacy brominated flame retardants in snakes and frogs: Tissue distribution, biomagnification, and maternal transfer

Although many studies have examined polybrominated diphenyl ethers (PBDEs) and novel brominated flame retardants (NBFRs) in biota, information on the bioaccumulation characteristics of NBFRs from field works is limited. This study investigated the tissue-specific exposure to PBDEs and NBFRs in two reptilian (short-tailed mamushi and red-backed rat snake) and one amphibian species (black-spotted frog) prevalent in the Yangtze River Delta, China. The levels of ΣPBDEs and ΣNBFRs ranged from 4.4–250 and 2.9–22 ng/g lipid weight for snakes respectively and 2.9–120 and 7.1–97 ng/g lipid weight for frogs respectively. BDE-209, BDE-154, and BDE-47 were three major PBDE congeners while decabromodiphenylethane (DBDPE) dominated in NBFRs. Tissue burdens indicated that snake adipose was the major storage site of PBDEs and NBFRs. The biomagnification factors (BMFs) estimated from black-spotted frog to red-backed rat snake indicated the biomagnification of penta- to nona-BDE congeners (BMFs 1.1–4.0) but the lack of biomagnification of other BDE and all NBFR congeners (BMFs 0.16–0.78). Mother to egg transfer of PBDEs and NBFRs evaluated in frogs showed that maternal transfer efficiency was positively related to chemical lipophilicity. This is the first field study on the tissue distribution of NBFRs in reptiles and amphibians and the maternal transfer behavior of 5 major NBFRs. The results underline the bioaccumulation potential of alternative NBFRs.

Inhibition of Resveratrol Analogs on Human and Rat 3β-Hydroxysteroid Dehydrogenases: Structure–Activity Relationship and Docking Analysis

Resveratrol and its analogs are phytochemicals. Human 3β-hydroxysteroid dehydrogenase 1 (3β-HSD1) synthesizes steroid hormones for normal pregnancy or promoting cancer metastasis. Whether they inhibit 3β-HSD1 remains unclear. In this study, the inhibitory potency, mode of action, structure-activity relationship, and docking parameters of resveratrol and its analogs on 3β-HSD1 and rat homolog 3β-HSD4 were analyzed. The inhibitory potency of these chemicals on human 3β-HSD1 was 4,4'-dihydroxystilbene (IC50, 3.68 μM) > pinostilbene (8.07 μM) > pinosylvin (10.60 μM) > lunularin (26.84 μM) > resveratrol (30.20 μM) > dihydroresveratrol (>100 μM) = oxyresveratrol (>100 μM) > dihydropinosylvin (ineffective at 100 μM). Resveratrol analogs and metabolites are mixed or competitive inhibitors of human 3β-HSD1. Resveratrol and 4,4'-dihydroxystilbene inhibited progesterone secretion by human JAr cells at ≥1 μM. Resveratrol (IC50, 32.09 μM) and pinosylvin (34.71 μM) significantly inhibited rat placental 3β-HSD4 activity. Docking analysis shows that resveratrol analogs and metabolites bind the steroid-binding sites of human 3β-HSD1 and rat 3β-HSD4 and interact with the catalytic residues Ser125/Thr125 and Tyr155. The negative correlation of LogP and IC50 values for human 3β-HSD1 indicates that lipophilicity of chemicals plays a critical role in the inhibitory effect of chemicals. In conclusion, 4,4'-dihydroxystilbene, pinostilbene, and pinosylvin effectively inhibit human 3β-HSD1 depending on their lipophilicity, thereby acting as potential therapeutic agents.

Pharmaceuticals and personal care products (PPCPs) in surface water and fish from three Asian countries: Species-specific bioaccumulation and potential ecological risks

In Asian developing countries, undeveloped and ineffective sewer systems are causing surface water pollution by a lot of contaminants, especially pharmaceuticals and personal care products (PPCPs). Therefore, the risks for freshwater fauna need to be assessed. The present study aimed at: i) elucidating the contamination status; ii) evaluating the bioaccumulation; and iii) assessing the potential risks of PPCP residues in surface water and freshwater fish from three Asian countries. We measured 43 PPCPs in the plasma of several fish species as well as ambient water samples collected from India (Chennai and Bengaluru), Indonesia (Jakarta and Tangerang), and Vietnam (Hanoi and Hoa Binh). In addition, the validity of the existing fish blood–water partitioning model based solely on the lipophilicity of chemicals is assessed for ionizable and readily metabolizable PPCPs. When comparing bioaccumulation factors calculated from the PPCP concentrations measured in the fish and water (BAFmeasured) with bioconcentration factors predicted from their pH-dependent octanol–water partition coefficient (BCFpredicted), close values (within an order of magnitude) were observed for 58–91 % of the detected compounds. Nevertheless, up to 110 times higher plasma BAFmeasured than the BCFpredicted were found for the antihistamine chlorpheniramine in tilapia but not in other fish species. The plasma BAFmeasured values of the compound were significantly different in the three fish species (tilapia > carp > catfish), possibly due to species-specific differences in toxicokinetics (e.g., plasma protein binding and hepatic metabolism). Results of potential risk evaluation based on the PPCP concentrations measured in the fish plasma suggested that chlorpheniramine, triclosan, haloperidol, triclocarban, diclofenac, and diphenhydramine can pose potential adverse effects on wild fish. Results of potential risk evaluation based on the PPCP concentrations measured in the surface water indicated high ecological risks of carbamazepine, sulfamethoxazole, erythromycin, and triclosan on Asian freshwater ecosystems.

Chemical Lipophilization of Bovine α-Lactalbumin with Saturated Fatty Acyl Residues: Effect on Structure and Functional Properties.

Bovine α-lactalbumin (α-LA) was chemically modified by the covalent attachment of fatty acid residues of different length (lauroyl, palmitoyl, and stearoyl) to modify its functional and antioxidant properties. Structural changes, functional properties, and antioxidant capacity in the pH interval between 3 and 10 were analyzed. Surface properties were improved. The esterification increased the hydrophobic interactions leading to a reduction in the solubility dependent on the incorporation ratio of the fatty acid residues. Improvement in emulsifying, foaming, and antioxidant properties were observed when the length of the fatty acid chains was short and mostly at a basic pH. With these results in mind, experiments could be conducted for the technological applications of these derivatives in the food, pharmaceutical, and cosmetic industries.

Bioactivity and Functionality of Anthocyanins: A Review

:Anthocyanins are flavonoid compounds imparting pink, red, blue, and purple colors to fruits, flowers, leaves, and some underground organs. These pigments play an important role in pollination and fruit and seed dispersal and they are related to the protection of plant tissues exposed to biotic and/or abiotic stress. Their consumption has been linked to diverse health benefits such as anti-inflammatory and anti-carcinogenic properties, diminution of cardiovascular disease incidence, obesity control, and diabetes mitigation effects. Also, in vitro studies have revealed certain potential cancer chemopreventive activities of anthocyanins. Reactive oxygen species scavenging as well as metal chelating and direct binding to proteins have been associated with anthocyanin health effects. Recent studies have indicated that these compounds can modulate decisive signaling pathways and gene regulation. Their action contributes to vascular homeostasis and to angiogenesis, inflammation, and platelet aggregation control. Likewise, anthocyanins have been associated with the prevention of a peroxynitrite-mediated disorder in endothelial cells. The potential use of anthocyanins as colorants in food has been extensively analyzed since they are the main hydrosoluble plant pigments. However, their instability and the influence of concentration, pH, temperature, and the presence of other compounds (phenolic acids, metals) on color properties can limit anthocyanin use as food ingredients and additives. Encapsulation has been proposed as an alternative to reduce food-processing damage and to deliver these compounds to their target site in the human body. Likewise, chemical lipophilization of anthocyanins has been assayed to obtain modified compounds with higher lipophilicity, more suitable for lipid-rich matrices.

Theoretical Characterization by Density Functional Theory (DFT) of Delphinidin 3-O-Sambubioside and Its Esters Obtained by Chemical Lipophilization.

Anthocyanins are water-soluble phenolic pigments. However, their poor solubility in lipidic media limits their use. This hurdle can be overcome with the lipophilization of anthocyanins, which consists of adding an aliphatic chain to a hydrophilic compound, in order to increase its solubility in lipids. Still, the unspecific chemical lipophilization of anthocyanin-esters produces molecules with different properties from their precursors. In this work, experimental changes of anthocyanin-esters obtained by chemical lipophilization are investigated in silico aiming specifically at observing their molecular behavior and comparing it with their anthocyanin precursor. Thus, the analysis of delphinidin 3-O-sambubioside and its esters employing Density Functional Theory (DFT) methods, such as the hybrid functional B3LYP in combination with the 6-31++G(d,p) Pople basis set, provides the ground state properties, the local reactivity and the molecular orbitals (MOs) of these compounds. Excited states properties were analyzed by TD-DFT with the B3LYP functional, and the M06 and M06-2X meta-GGA functionals. Local reactivity calculations showed that the electrophilic site for all the anthocyanin-esters was the same as the one for the anthocyanin precursor, however the nucleophilic site changed depending localization of the esterification. TD-DFT results indicate that the place of esterification could change the electronic transitions and the MOs spatial distribution.

Predicting Passive and Active Tissue:Plasma Partition Coefficients: Interindividual and Interspecies Variability

A mechanistic tissue composition model incorporating passive and active transport for the prediction of steady-state tissue:plasma partition coefficients (K(t:pl)) of chemicals in multiple mammalian species was used to assess interindividual and interspecies variability. This approach predicts K(t:pl) using chemical lipophilicity, pKa, phospholipid membrane binding, and the unbound plasma fraction, together with tissue fractions of water, neutral lipids, neutral and acidic phospholipids, proteins, and pH. Active transport K(t:pl) is predicted using Michaelis-Menten transport parameters. Species-specific biological properties were identified from 126 peer reviewed journal articles, listed in the Supporting Information, for mouse, rat, guinea pig, rabbit, beagle dog, pig, monkey, and human species. Means and coefficients of variation for biological properties were used in a Monte Carlo analysis to assess variability. The results show K(t:pl) interspecies variability for the brain, fat, heart, kidney, liver, lung, muscle, red blood cell, skin, and spleen, but uncertainty in the estimates obscured some differences. Compounds undergoing active transport are shown to have concentration-dependent K(t:pl). This tissue composition-based mechanistic model can be used to predict K(t:pl) for organic chemicals across eight species and 10 tissues, and can be an important component in drug development when scaling K(t:pl) from animal models to humans.

A comparison of octanol–water partitioning between organic chemicals and their metabolites in mammals

Bioaccumulation models take various elimination and uptake processes into account, estimating rates from chemical lipophilicity, expressed as the octanol–water partition ratio (Kow). Here, we focussed on metabolism, which transforms parent compounds into usually more polar metabolites, thus enhancing elimination. The aim of this study was to quantify the change in lipophilicity of relevant organic pollutants undergoing various biotransformation reactions in mammals. We considered oxidation reactions catalyzed by three enzyme groups: cytochrome P450 (CYP), alcohol dehydrogenase (ADH), and aldehyde dehydrogenase (ALDH). Estimated logKow values of a selected dataset of parent compounds were compared with the logKow of their first metabolites. The logKow decreased by a factor that varies between 0 and −2, depending on the metabolic pathway. For reactions mediated by CYP, the decrease in Kow was one order of magnitude for hydroxylated and epoxidated compounds and two orders of magnitude for dihydroxylated and sulphoxidated xenobiotics. On the other hand, no significant change in lipophilicity was observed for compounds N-hydroxylated by CYP and for alcohols and aldehydes metabolized by ADH and ALDH. These trends could be anticipated by the calculus method of logKow. Yet, they were validated using experimental logKow values, when available. These relationships estimate the extent to which the elimination of pollutants is increased by biotransformation. Thus, the quantification of the Kow reduction can be considered as a first necessary step in an alternative approach to anticipate biotransformation rates, which are hard to estimate with existing methods.

Measurement of Drug Lipophilicity and pKa Using Acoustics

Lipophilicity of chemicals and drug candidates is normally described in terms of octanol/water partitioning and log P. We investigated an alternate approach to lipophilicity determination using a mimic of an alkyl alcohol with compound partitioning quantified using acoustic sensing. A self-assembled monolayer composed of HSC(10)(CH(2)CH(2)O)(6)C(18) was formed on planar gold electrodes of a piezoelectric acoustic sensor. The system was challenged with compounds covering a 4-log range of log D values. As compounds partitioned in the interfacial layer, changes in sensor resonant frequency were found to correlate with compound partition coefficients (log P) and with distribution coefficients (log D). Linear concordance (R(2) = 0.933) was established between log(-dF/M(w)t) and log P and with log D in both water and biological buffers at variant pH (pH 5.2 to 7.8). In turn, drug pK(a) could be determined by profiling log D changes during pH titration. The lipophilicity/pH profile of a weakly basic drug (quinine; pK(a) = 7.95) was sigmoidal with respect to -dF/M(w) values, with a profile inverse to that of a weakly acidic drug (naproxen; pK(a) = 4.15).

A Mass Balance of Tri-Hexabrominated Diphenyl Ethers in Lactating Cows

Beef and dairy products can be important vectors of human exposure to polybrominated diphenylethers (BDEs), and hence an understanding of BDE transfer from feed to cows' milk and tissue is important for BDE exposure assessment The fate of tri- to hexaBDEs in lactating cows exposed to a naturally contaminated diet was studied by analyzing feed, feces, and milk samples from a mass balance study. Tissue distribution was studied in one cowslaughtered afterthe experiment The carryover rates from feed to milk ranged from 0.15 to 0.35 for the major congeners. Lower values were observed for several of the tetrabrominated congeners, and this was attributed to metabolism. The dietary absorption efficiency decreased with increasing octanol-water partition coefficient of the BDE congener. The absorption behavior was consistent with a model based on chemical lipophilicity, but agreed less well with a model based on effective molecular diameter, and it violated Lipinski's "rule of 5". The lipid normalized concentrations were similar in all tissues analyzed including liver and milk, suggesting that tissue distribution is governed by partitioning into lipids. Overall, the behavior of the tri- to hexaBDEs was consistent with that observed for other classes of halogenated aromatic contaminants such as PCBs and PCDD/Fs, but it differed markedly from the behavior of the hepta- decaBDEs.

Some molecular descriptors for non-specific chromosomal genotoxicity based on hydrophobic interactions

A concept relating the lipophilicity of chemicals with their genotoxicity on a chromosomal level had been generated by Schultz and Onfelt (Chem Biol Interact 126:97-123, 2000). It was shown that aneuploidy in Chinese hamster V79 cells was elicited by lipophilic chemicals at concentrations related to their hydrophobicity (log P), whereas toxicants with a specific mode of action acted at concentrations consistently lower than predicted based on log P. We have now combined available data sets on aneuploidy/micronucleus formation with procedures used in QSAR modelling, in order to find new molecular descriptors for modelling non-specific chromosomal genotoxicity, and to optimise combinations thereof. Molecular structures of 26 chemicals, including steroids, were converted into single 3D models using Corina (version 3.20), and 11 descriptors of molecular properties were calculated. The data of 16 compounds assigned to a non-specific mode of action were imported into the QSAR module of the software package Cerius(2) (version 4.10). Applying genetic function approximation (GFA), linear equations were set up relating molecular descriptors with experimental concentrations at which doubling of micronuclei occurred in V79 cells (exp -log C). The number of variables (molecular descriptors) was limited to a maximum of three, and linear and quadratic terms were allowed. Based on the descriptions provided by the GFA procedure, log P was the most suitable single property to describe non-specific genotoxicity [r (2 ) = 0.88], confirming the original concept of Schultz and Onfelt. Using more descriptors (up to three in combination) resulted in an optimization of correlations up to r (2 )= 0.97. Such optimal correlation coefficients were obtained by combinations (a) of the numbers of hydrogen bond acceptors, the polar surface and total surface areas of molecules on one hand, and by (b) the dipole moment, polar surface and total surface descriptors on the other hand. In essence, the relation of polar surface to the total molecular surface appears pivotal to determine the non-specific chromosomal genotoxicity of lipophilic compounds.

Application of associative neural networks for prediction of lipophilicity in ALOGPS 2.1 program.

This article provides a systematic study of several important parameters of the Associative Neural Network (ASNN), such as the number of networks in the ensemble, distance measures, neighbor functions, selection of smoothing parameters, and strategies for the user-training feature of the algorithm. The performance of the different methods is assessed with several training/test sets used to predict lipophilicity of chemical compounds. The Spearman rank-order correlation coefficient and Parzen-window regression methods provide the best performance of the algorithm. If additional user data is available, an improved prediction of lipophilicity of chemicals up to 2-5 times can be calculated when the appropriate smoothing parameters for the neural network are selected. The detected best combinations of parameters and strategies are implemented in the ALOGPS 2.1 program that is publicly available at http://www.vcclab.org/lab/alogps.

COMPARISON OF MODELS FOR THE ESTIMATION OF BIOLOGICAL PARTITION COEFFICIENTS

Several models have been published for calculating blood-air, tissue-air, or tissue-blood partition coefficients of volatile organic chemicals in human or rat tissues, from functions of their octanol-water partition coefficients or solubilities in vegetable oil and water. In this work, the relative accuracy, strengths, and limitations of the various models are examined. Comparison of predicted human tissue-air and tissue-blood partition coefficients with experimental values has been made for 12 chemicals, covering a wide range of lipophilicity (acetone, isopropanol, diethylether, methylene dichloride, benzene, toluene, trichloroethylene, trichloroethane, n-pentane, cyclohexane, n-hexane, and n-heptane). Seven published models for human tissue-air and 10 models for tissue-blood partition coefficients have been compared. Fewer models are available for predicting rat tissue-air and rat tissue-blood partition coefficients, but a similar comparison has been made. The ratio of predicted to experimental partition coefficients and their mean, R mean , and the mean magnitude of the difference between predicted and experimental values of log 10 P, E, were used to assess the accuracy of each model. For the test set the most accurate for human blood-air partition coefficients were the empirical equations of Meulenberg and Vijverberg (R mean = 1.1 - 0.46, E = 0.156) and the empirical solvation equation of Abraham and Weathersby (1994) (R mean = 0.93 - 0.38, E = 0.166). For rat blood, predictions are much less accurate due to difficulties in modeling the effects of protein binding, which are much larger. Overall, for rat blood-air partition coefficients the equation of Meulenberg and Vijverberg (1999) (R mean = 0.74 - 0.50, E = 0.236) was the most accurate. The tissue-composition-based equations of Poulin and Krishnan, using solubilities in vegetable oil, performed well for human liver-air partition coefficients (R mean = 1.21 - 0.28, E = 0.079) for log(octanol-water partition coefficients) > 0.7 and for fat-air partition coefficients, but overestimated solubilities in human kidney and brain tissues (e.g., for kidney tissue, R = 1.88 - 0.58, E = 0.255). The equations of Meulenberg and Vijverberg (2000a), Abraham and Weathersby (1994), and Paterson and Mackay (1989) also performed moderately well for human tissue-air partition coefficients. For rat muscle-air, liver-air, and fat-air partition coefficients the model of Poulin and Krishnan (1996a) gave the most accurate predictions. For tissue-blood partition coefficients, generally good agreement with experimental values is obtained by the empirical model of Balaz and Lukacova (1999) (e.g., for human kidney, R mean = 1.15 - 0.38, E = 0.085) and, if solubility in fat is known, by the equations of Fiserova-Bergerova and Diaz (1986) (e.g., for human muscle, R mean = 1.10 - 0.39, E = 0.107). The equations of DeJongh et al. (1997) gave the most accurate predictions for rat muscle-blood, liver-blood and fat-blood partition coefficients (e.g., for rat muscle R mean = 1.03 - 0.39, E = 0.149), but predictions were less accurate than for human tissue-blood partition coefficients, attributable to difficulties in modeling the effect of protein binding. The choice of equation for use in physiologically based pharmacokinetic (PBPK) models depends on the species, tissue, and chemical lipophilicity.

Chemical lipophilization of soy protein isolates and wheat gluten

Chemical lipophilization of soy protein isolates and wheat gluten

Chemical lipophilization of soy protein isolates and wheat gluten

Chemical modification of soy protein isolate and wheat gluten can be used to investigate the influence of the chemical composition and the structure of the proteins on the final product properties and to adjust these properties to meet specific demands. Proteins were lipophilized by adding different levels of lauroyl chloride to aqueous protein dispersions. At optimum reaction conditions, incorporation rates of lauroyl chains to the protein were 400 and 300 μmol/g proteins for soy protein isolate and wheat gluten, respectively. The study showed that it was possible to lipophilize proteins in an aqueous medium, even with the protein significantly high in concentration.

Characterization of Renal Brush-Border and Basolateral Membrane Transporters for Organic Cations

The renal proximal tubule is the site of active secretion of a diverse array of organic cations and bases (collectively, OCs). The basolateral entry step in transtubule OC transport involves an electrogenic facilitated diffusion process. OC exit into the tubule lumen is the active step in secretion and involves the carrier-mediated exchange of OC for H⁺. The specificity of these two processes is influenced less by steric characteristics of substrates than by their chemical lipophilicity, with both transporters displaying an increasing affinity for OCs of increasing lipophilicity. Several additional OC transporters exist within each membrane and the concerted activity of these processes permits the proximal tubule to effect the secretion of most OCs, and the selective reabsorption of others, and provides the tubule with a degree of ‘redundancy’ in the means available for secreting potentially toxic xenobiotic compounds from the body.

化学的油性化によるタンパク質への親油特性の付与

化学的油性化によるタンパク質への親油特性の付与