Passive Permeability of Planar Lipid Bilayers to Organic Anions

Ebert, Andrea; Hannesschlaeger, Christof; Goss, Kai‐Uwe; Pohl, Peter

doi:10.1016/j.bpj.2018.09.025

Cited by 41 publications

(68 citation statements)

References 53 publications

(72 reference statements)

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“…The pH dependence of the intrinsic uncoupling activity has been described by a kinetic model (Escher et al ), and QSARs exist for the prediction of the intrinsic uncoupling activity that are focused on the rate‐limiting step of the uncoupling process, the permeation of the charged species across the membrane (Spycher et al , ). The permeability of the lipid bilayer can also be measured in independent experiments or predicted from physicochemical descriptors (Ebert et al ).…”

Section: Ecotoxicity Prediction Modelsmentioning

confidence: 99%

Recommendations for Improving Methods and Models for Aquatic Hazard Assessment of Ionizable Organic Chemicals

Escher

Abagyan

Embry

et al. 2020

Enviro Toxic and Chemistry

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Ionizable organic chemicals (IOCs) such as organic acids and bases are an important substance class requiring aquatic hazard evaluation. Although the aquatic toxicity of IOCs is highly dependent on the water pH, many toxicity studies in the literature cannot be interpreted because pH was not reported or not kept constant during the experiment, calling for an adaptation and improvement of testing guidelines. The modulating influence of pH on toxicity is mainly caused by pHdependent uptake and bioaccumulation of IOCs, which can be described by ion-trapping and toxicokinetic models. The internal effect concentrations of IOCs were found to be independent of the external pH because of organisms' and cells' ability to maintain a stable internal pH milieu. If the external pH is close to the internal pH, existing quantitative structure-activity relationships (QSARs) for neutral organics can be adapted by substituting the octanol-water partition coefficient by the ionization-corrected liposome-water distribution ratio as the hydrophobicity descriptor, demonstrated by modification of the target lipid model. Charged, zwitterionic and neutral species of an IOC can all contribute to observed toxicity, either through concentration-additive mixture effects or by interaction of different species, as is the case for uncoupling of mitochondrial respiration. For specifically acting IOCs, we recommend a 2-step screening procedure with ion-trapping/QSAR models used to predict the baseline toxicity, followed by adjustment using the toxic ratio derived from in vitro systems. Receptor-or plasmabinding models also show promise for elucidating IOC toxicity. The present review is intended to help demystify the ecotoxicity of IOCs and provide recommendations for their hazard and risk assessment. Environ Toxicol Chem 2020;39:269-286. /ETC FIGURE 1: Speciation in relation to the pH and acid dissociation constant, pK a , for (A) monoprotic acids and (B) monoprotic bases. The experimentally accessible pH range is marked by blue (fish) and green (daphnia, algae) boxes. Further discussion on the experimentally accessible pH range is provided in the section Testing guidelines.

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Section: Ecotoxicity Prediction Modelsmentioning

confidence: 99%

Recommendations for Improving Methods and Models for Aquatic Hazard Assessment of Ionizable Organic Chemicals

Escher

Abagyan

Embry

et al. 2020

Enviro Toxic and Chemistry

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“…We obtained P = (5.70 ± 0.14) × 10 −11 cm s −1 from the linear increase in G m ( Fig. 2, B ) by using the Goldman-Hodkin-Katz flux equation [ 46 ]. The permeability of Na + ((0.5–2.9) × 10 −14 cm s −1 [ 47 ]) in intact phospholipid bilayers is several orders of magnitude lower than that of H + (~ (0.3–1.8) × 10 −6 cm s −1 [ 48 , 49 ]), and therefore is independent of the Na + concentration in buffer ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Covalent modification of phosphatidylethanolamine by 4-hydroxy-2-nonenal increases sodium permeability across phospholipid bilayer membranes

Jovanović

Škulj

Pohl

et al. 2019

Free Radical Biology and Medicine

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Reactive aldehydes (RAs), such as 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE), produced by cells under conditions of oxidative stress, were shown to react with phosphatidylethanolamine (PE) in biological and artificial membranes. They form RA-PE adducts, which affect the function of membrane proteins by modifying various biophysical properties of the membrane. The ratio of protein to lipid in biological membranes is different, but can reach 0.25 in the membranes of oligodendrocytes. However, the impact of RA-PE adducts on permeability ( P ) of the neat lipid phase and molecular mechanism of their action are poorly understood. In this study, we showed that HNE increased the membrane P for ions, and in particular for sodium. This effect depended on the presence of DOPE, and was not recorded for the more toxic compound, ONE. Molecular dynamics simulations suggested that HNE-PE and ONE-PE adducts anchored different positions in the lipid bilayer, and thus changed the membrane lipid area and bilayer thickness in different ways. Sodium permeability, calculated in the presence of double HNE-PE adducts, was increased by three to four orders of magnitude when compared to P Na in adduct – free membranes. A novel mechanism by which HNE alters permeability of the lipid membrane may explain the multiple toxic or regulative effects of HNE on the function of excitable cells, such as neurons, cardiomyocytes and neurosensory cells under conditions of oxidative stress.

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“…Several mechanisms that could lower Ci below the equilibrium value were considered. The low pKa values of the acids (3.66–4.48) mean that at pHe 6.5, concentrations of the membrane-permeant (neutral) free acids would be ~0.1–1% of the total, while the anions are expected to have negligible membrane permeability [63], resulting in low logD values and slow kinetics of uptake into cells. Despite this, there was no obvious trend in Ci values between 5 min and 60 min (Table 8).…”

Section: Discussionmentioning

confidence: 99%

Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in Tumors

et al. 2019

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Extracellular acidification is an important feature of tumor microenvironments but has yet to be successfully exploited in cancer therapy. The reversal of the pH gradient across the plasma membrane in cells that regulate intracellular pH (pHi) has potential to drive the selective uptake of weak acids at low extracellular pH (pHe). Here, we investigate the dual targeting of low pHe and hypoxia, another key feature of tumor microenvironments. We prepared eight bioreductive prodrugs based on the benzotriazine di-oxide (BTO) nucleus by appending alkanoic or aminoalkanoic acid sidechains. The BTO acids showed modest selectivity for both low pHe (pH 6.5 versus 7.4, ratios 2 to 5-fold) and anoxia (ratios 2 to 8-fold) in SiHa and FaDu cell cultures. Related neutral BTOs were not selective for acidosis, but had greater cytotoxic potency and hypoxic selectivity than the BTO acids. Investigation of the uptake and metabolism of representative BTO acids confirmed enhanced uptake at low pHe, but lower intracellular concentrations than expected for passive diffusion. Further, the modulation of intracellular reductase activity and competition by the cell-excluded electron acceptor WST-1 suggests that the majority of metabolic reductions of BTO acids occur at the cell surface, compromising the engagement of the resulting free radicals with intracellular targets. Thus, the present study provides support for designing bioreductive prodrugs that exploit pH-dependent partitioning, suggesting, however, that that the approach should be applied to prodrugs with obligate intracellular activation.

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Passive Permeability of Planar Lipid Bilayers to Organic Anions

Cited by 41 publications

References 53 publications

Recommendations for Improving Methods and Models for Aquatic Hazard Assessment of Ionizable Organic Chemicals

Recommendations for Improving Methods and Models for Aquatic Hazard Assessment of Ionizable Organic Chemicals

Covalent modification of phosphatidylethanolamine by 4-hydroxy-2-nonenal increases sodium permeability across phospholipid bilayer membranes

Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in Tumors

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