Modelling an alternative lipophilicity scale of bisphenols using biomimetic chromatography: Relevance to membrane-driven baseline toxicity: Original scientific paper

Krzesimir  Ciura; Julia  Nicman; Szymon  Zdybel; Giacomo  Russo; Lucia  Grumetto; Katarzyna Ewa Greber; Anita Sosnowska; Joanna  Dołżonek; Karolina  Jagiello

doi:10.5599/admet.3169

Authors

Krzesimir Ciura Department of Physical Chemistry, Faculty of Pharmacy, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416, Gdańsk, Poland and Laboratory of Environmental Chemoinformatics, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308, Gdansk, Poland https://orcid.org/0000-0001-6187-6039
Julia Nicman Department of Physical Chemistry, Faculty of Pharmacy, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416, Gdańsk, Poland https://orcid.org/0009-0000-7120-7218
Szymon Zdybel Laboratory of Environmental Chemoinformatics, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308, Gdansk, Poland and QSAR Lab Ltd., Trzy Lipy 3 St., 80-172 Gdańsk, Poland https://orcid.org/0000-0002-9640-3810
Giacomo Russo School of Applied Sciences, Sighthill Campus, Edinburgh Napier University, 9 Sighthill Ct, EH11 4BN Edinburgh, United Kingdom https://orcid.org/0000-0002-2964-389X
Lucia Grumetto Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via D. Montesano, 49, 80131, Naples, Italy https://orcid.org/0000-0002-3529-1819
Katarzyna Ewa Greber Department of Physical Chemistry, Faculty of Pharmacy, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416, Gdańsk, Poland https://orcid.org/0000-0002-7820-0390
Anita Sosnowska Laboratory of Environmental Chemoinformatics, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308, Gdansk, Poland and QSAR Lab Ltd., Trzy Lipy 3 St., 80-172 Gdańsk, Poland https://orcid.org/0000-0003-3288-4309
Joanna Dołżonek Department of Environmental Analysis, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308, Gdansk, Poland https://orcid.org/0000-0001-5595-7764
Karolina Jagiello Laboratory of Environmental Chemoinformatics, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308, Gdansk, Poland and QSAR Lab Ltd., Trzy Lipy 3 St., 80-172 Gdańsk, Poland https://orcid.org/0000-0002-2730-6873

DOI:

https://doi.org/10.5599/admet.3169

Keywords:

Immobilized artificial membrane, phospholipid affinity, endocrine disruptors, baseline toxicity, sphingomyelin column

Abstract

Background and purpose: Bisphenol A and its structural analogues are ubiquitous environmental contaminants and potential endocrine disruptors, creating a need for mechanistically relevant descriptors that support early hazard assessment. This study asked whether lipophilicity indices derived from biomimetic chromatography better reflect baseline toxicity and membrane-relevant behaviour of bisphenols than commonly used in silico log P / log D descriptors. Experimental approach: A set of 18 bisphenol derivatives was analysed using phosphatidylcholine- and sphingomyelin-functionalised stationary phases and a conventional C18 column to obtain chromatographic hydrophobicity indices, which were then compared with predicted log P / log D values and related to mechanistically diverse toxicity endpoints (in vitro cytotoxicity in mammalian cells, ex vivo cardiotoxicity assessed as vasodilation, and aquatic toxicity towards Daphnids). Key results: Biomimetic chromatographic indices showed consistently stronger and more coherent relationships with biological activity than theoretical descriptors. They also uniquely captured structural effects, such as positional isomerism, which were largely indistinguishable using theoretical lipophilicity indices. Conclusion: These findings support biomimetic chromatography as an early-tier IATA tool, providing membrane-relevant experimental indices linking bisphenol lipophilicity with baseline toxicity.

Downloads

Download data is not yet available.

References

[1] A. Mishra, D. Goel, S. Shankar. Bisphenol A contamination in aquatic environments: a review of sources, environmental concerns, and microbial remediation. Environmental Monitoring and Assessment 195 (2023) 1352. https://doi.org/10.1007/s10661-023-11977-1 DOI: https://doi.org/10.1007/s10661-023-11977-1

[2] K.E. Pelch, Y. Li, L. Perera, K.A. Thayer, K.S. Korach. Characterization of Estrogenic and Androgenic Activities for Bisphenol A-like Chemicals (BPs): In Vitro Estrogen and Androgen Receptors Transcriptional Activation, Gene Regulation, and Binding Profiles. Toxicological Sciences 172 (2019) 23-37. https://doi.org/10.1093/toxsci/kfz173 DOI: https://doi.org/10.1093/toxsci/kfz173

[3] M. Maniradhan, L. Calivarathan. Bisphenol A-Induced Endocrine Dysfunction and its Associated Metabolic Disorders. Endocrine, Metabolic & Immune Disorders - Drug Targets 23 (2023) 515-529. https://doi.org/10.2174/1871530322666220928144043 DOI: https://doi.org/10.2174/1871530322666220928144043

[4] N.G. Khan, J. Correia, D. Adiga, P.S. Rai, H.S. Dsouza, S. Chakrabarty, S.P. Kabekkodu. A comprehensive review on the carcinogenic potential of bisphenol A: clues and evidence. Environmental Science and Pollution Research 28 (2021) 19643-19663. https://doi.org/10.1007/s11356-021-13071-w DOI: https://doi.org/10.1007/s11356-021-13071-w

[5] O. Adamovsky, K.J. Groh, A. Białk-Bielińska, B.I. Escher, R. Beaudouin, L.M. Lagares, K.E. Tollefsen, M. Fenske, E. Mulkiewicz, N. Creusot, A. Sosnowska, S. Loureiro, J. Beyer, G. Repetto, A. Štern, I. Lopes, M. Monteiro, A. Zikova-Kloas, T. Eleršek, M. Vračko, S. Zdybel, T. Puzyn, W. Koczur, J.E. Morthorst, H. Holbech, G. Carlsson, S. Örn, Ó. Herrero, A. Siddique, M. Liess, G. Braun, V. Srebny, B. Žegura, N. Hinfray, F. Brion, D. Knapen, E. Vandeputte, E. Stinckens, L. Vergauwen, L. Behrendt, M.J. Silva, L. Blaha, K. Kyriakopoulou. Exploring BPA alternatives - Environmental levels and toxicity review. Environment International 189 (2024) 108728. https://doi.org/10.1016/j.envint.2024.108728 DOI: https://doi.org/10.1016/j.envint.2024.108728

[6] G. Russo, A. Capuozzo, F. Barbato, C. Irace, R. Santamaria, L. Grumetto. Cytotoxicity of seven bisphenol analogues compared to bisphenol A and relationships with membrane affinity data. Chemosphere 201 (2018) 432-440. https://doi.org/10.1016/j.chemosphere.2018.03.014 DOI: https://doi.org/10.1016/j.chemosphere.2018.03.014

[7] Q.-S. Sheng, B. Liu, X. Wang, L. Hua, S.-C. Zhao, X.-Z. Sun, M.-Y. Li, X.-Y. Zhang, J.-X. Wang, P.-L. Hu. Revolutionizing toxicological risk assessment: integrative advances in new approach methodologies (NAMs) and precision toxicology. Archives of Toxicology 99 (2025) 4697-4707. https://doi.org/10.1007/s00204-025-04169-y DOI: https://doi.org/10.1007/s00204-025-04169-y

[8] H. Jaeschke, A. Ramachandran. Are New Approach Methodologies (NAMs) the Holy Grail of toxicology? Toxicological Sciences 208 (2025) 1-8. https://doi.org/10.1093/toxsci/kfaf113 DOI: https://doi.org/10.1093/toxsci/kfaf113

[9] OECD. Overview of Concepts and Available Guidance related to Integrated Approaches to Testing and Assessment (IATA). OECD Series on Testing and Assessment 329 (2020). https://doi.org/10.1787/cd920ca4-en DOI: https://doi.org/10.1787/cd920ca4-en

[10] H. Meyer. Zur Theorie der Alkoholnarkose. Archiv für experimentelle Pathologie und Pharmakologie 42 (1899) 109-118. https://doi.org/10.1007/bf01834479 DOI: https://doi.org/10.1007/BF01834479

[11] C. Hansch, A.R. Steward, J. Iwasa, E.W. Deutsch. The Use of a Hydrophobic Bonding Constant for Structure-Activity Correlations. Molecular Pharmacology 1 (1965) 205-213. https://doi.org/10.1016/S0026-895X(25)14764-0 DOI: https://doi.org/10.1016/S0026-895X(25)14764-0

[12] W.R. Glave, C. Hansch. Relationship between Lipophilic Character and Anesthetic Activity. Journal of Pharmaceutical Sciences 61 (1972) 589-591. https://doi.org/10.1002/jps.2600610420 DOI: https://doi.org/10.1002/jps.2600610420

[13] C. Pidgeon, U.V. Venkataram. Immobilized artificial membrane chromatography: Supports composed of membrane lipids. Analytical Biochemistry 176 (1989) 36-47. https://doi.org/10.1016/0003-2697(89)90269-8 DOI: https://doi.org/10.1016/0003-2697(89)90269-8

[14] K.L. Valko. Biomimetic chromatography-A novel application of the chromatographic principles. Analytical Sciences Advances 3 (2022) 146-153. https://doi.org/10.1002/ansa.202200004 DOI: https://doi.org/10.1002/ansa.202200004

[15] K.L. Valkó. Lipophilicity and biomimetic properties measured by HPLC to support drug discovery. Journal of Pharmaceutical and Biomedical Analysis 130 (2016) 35-54. https://doi.org/10.1016/j.jpba.2016.04.009 DOI: https://doi.org/10.1016/j.jpba.2016.04.009

[16] S. Bunnally, R.J. Young. The role and impact of high throughput biomimetic measurements in drug discovery. ADMET & DMPK 6 (2018) 74-84. https://doi.org/10.5599/admet.530 DOI: https://doi.org/10.5599/admet.530

[17] C. Stergiopoulos, F. Tsopelas, M. Ochsenkühn-Petropoulou, K. Valko. Predicting the acute aquatic toxicity of organic UV filters used in cosmetic formulations. ADMET & DMPK 12 (2024) 781-796. https://doi.org/10.5599/admet.2364 DOI: https://doi.org/10.5599/admet.2364

[18] C. Stergiopoulos, F. Tsopelas, K. Valko. Prediction of hERG inhibition of drug discovery compounds using biomimetic HPLC measurements. ADMET & DMPK 9 (2021) 191-207. https://doi.org/10.5599/admet.995 DOI: https://doi.org/10.5599/admet.995

[19] G. Russo, L. Grumetto, R. Szucs, F. Barbato, F. Lynen. Screening therapeutics according to their uptake across the blood-brain barrier: A high throughput method based on immobilized artificial membrane liquid chromatography-diode-array-detection coupled to electrospray-time-of-flight mass spectrometry. European Journal of Pharmaceutics and Biopharmaceutics 127 (2018) 72-84. https://doi.org/10.1016/j.ejpb.2018.02.004 DOI: https://doi.org/10.1016/j.ejpb.2018.02.004

[20] S. Kovačević, M.K. Banjac, N. Milošević, J. Ćurčić, D. Marjanović, N. Todorović, J. Krmar, S. Podunavac-Kuzmanović, N. Banjac, G. Ušćumlić. Comparative chemometric and quantitative structure-retention relationship analysis of anisotropic lipophilicity of 1-arylsuccinimide derivatives determined in high-performance thin-layer chromatography system with aprotic solvents. Journal of Chromatography A 1628 (2020) 461439. https://doi.org/10.1016/j.chroma.2020.461439 DOI: https://doi.org/10.1016/j.chroma.2020.461439

[21] I. Neri, M. Piccolo, G. Russo, M.G. Ferraro, V. Marotta, R. Santamaria, L. Grumetto. The combined use of biological investigations, bio chromatographic and in silico methods to solve the puzzle of badge and its derivative’s toxicity. Chemosphere 367 (2024) 143640. https://doi.org/10.1016/j.chemosphere.2024.143640 DOI: https://doi.org/10.1016/j.chemosphere.2024.143640

[22] F. Tsopelas, F. Stergiopoulos, A. Tsantili-Kakoulidou. Immobilized artificial membrane chromatography: from medicinal chemistry to environmental sciences. ADMET & DMPK 6 (2018) 225-241. https://doi.org/10.5599/admet.553 DOI: https://doi.org/10.5599/admet.553

[23] C. Stergiopoulos, D. Makarouni, A. Tsantili-Kakoulidou, M. Ochsenkühn-Petropoulou, F. Tsopelas. Immobilized artificial membrane chromatography as a tool for the prediction of ecotoxicity of pesticides. Chemosphere 224 (2019) 128-139. https://doi.org/10.1016/j.chemosphere.2019.02.075 DOI: https://doi.org/10.1016/j.chemosphere.2019.02.075

[24] A.W. Sobańska. Affinity of Compounds for Phosphatydylcholine-Based Immobilized Artificial Membrane—A Measure of Their Bioconcentration in Aquatic Organisms. Membranes 12 (2022) 1130. https://doi.org/10.3390/membranes12111130 DOI: https://doi.org/10.3390/membranes12111130

[25] A.W. Sobańska. RP-18 TLC retention data and calculated physico-chemical parameters as predictors of soil-water partition and bioconcentration of organic sunscreens. Chemosphere 279 (2021) 130527. https://doi.org/10.1016/j.chemosphere.2021.130527 DOI: https://doi.org/10.1016/j.chemosphere.2021.130527

[26] A.W. Sobańska. Evaluation of drug-likeness and ADME properties of sunscreens and preservatives using reversed-phase thin layer chromatographic retention data and calculated descriptors. Journal of Pharmaceutical and Biomedical Analysis 201 (2021) 114126. https://doi.org/10.1016/j.jpba.2021.114126 DOI: https://doi.org/10.1016/j.jpba.2021.114126

[27] K.L. Valko, T. Zhang. Biomimetic properties and estimated in vivo distribution of chloroquine and hydroxy-chloroquine enantiomers. ADMET & DMPK 9 (2021) 151-165. https://doi.org/10.5599/admet.929 DOI: https://doi.org/10.5599/admet.929

[28] D. Szulczyk, M. Woziński, M. Koliński, S. Kmiecik, A. Głogowska, E. Augustynowicz-Kopeć, M.A. Dobrowolski, P. Roszkowski, M. Struga, K. Ciura. Menthol- and thymol-based ciprofloxacin derivatives against Mycobacterium tuberculosis: in vitro activity, lipophilicity, and computational studies. Scientific Reports 13 (2023) 16328. https://doi.org/10.1038/s41598-023-43708-4 DOI: https://doi.org/10.1038/s41598-023-43708-4

[29] S. Ulenberg, K. Ciura, P. Georgiev, M. Pastewska, G. Ślifirski, M. Król, F. Herold, T. Bączek. Use of biomimetic chromatography and in vitro assay to develop predictive GA-MLR model for use in drug-property prediction among anti-depressant drug candidates. Microchemical Journal 175 (2022) 107183. https://doi.org/10.1016/j.microc.2022.107183 DOI: https://doi.org/10.1016/j.microc.2022.107183

[30] K. Ciura, S. Kovačević, M. Pastewska, H. Kapica, M. Kornela, W. Sawicki. Prediction of the chromatographic hydrophobicity index with immobilized artificial membrane chromatography using simple molecular descriptors and artificial neural networks. Journal of Chromatography A 1660 (2021) 462666. https://doi.org/10.1016/j.chroma.2021.462666 DOI: https://doi.org/10.1016/j.chroma.2021.462666

[31] G. Russo, G. Ermondi, G. Caron, D. Verzele, F. Lynen. Into the first biomimetic sphingomyelin stationary phase: Suitability in drugs’ biopharmaceutic profiling and block relevance analysis of selectivity. European Journal of Pharmaceutical Sciences 156 (2021) 105585. https://doi.org/10.1016/j.ejps.2020.105585 DOI: https://doi.org/10.1016/j.ejps.2020.105585

[32] V. Tvrdý, P. Dias, I. Nejmanová, A. Carazo, E. Jirkovský, J. Pourová, J. Fadraersada, M. Moravcová, L.P. Mašič, M.S. Dolenc, P. Mladěnka. The effects of bisphenols on the cardiovascular system ex vivo and in vivo. Chemosphere 313 (2023) 137565. https://doi.org/10.1016/j.chemosphere.2022.137565 DOI: https://doi.org/10.1016/j.chemosphere.2022.137565

[33] K.L. Valko, S. Nunhuck, C. Bevan, M.H. Abraham, D.P. Reynolds. Fast gradient HPLC method to determine compounds binding to human serum albumin. Relationships with octanol/water and immobilized artificial membrane lipophilicity. Journal of Pharmaceutical Sciences 92 (2003) 2236-2248. https://doi.org/10.1002/jps.10494 DOI: https://doi.org/10.1002/jps.10494

[34] K.L. Valko, S. Rava, S. Bunnally, S. Anderson. Revisiting the application of Immobilized Artificial Membrane (IAM) chromatography to estimate in vivo distribution properties of drug discovery compounds based on the model of marketed drugs. ADMET & DMPK 8 (2020) 78-97. https://doi.org/10.5599/admet.757 DOI: https://doi.org/10.5599/admet.757

[35] K. Ciura. Modeling of small molecule affinity to phospholipids using IAM-HPLC and a QSRR approach enhanced by similarity-based machine learning algorithms. Journal of Chromatography A 1714 (2024) 464549. https://doi.org/10.1016/j.chroma.2023.464549 DOI: https://doi.org/10.1016/j.chroma.2023.464549

[36] G. Matteo, K. Leingartner, A. Rowan-Carroll, M. Meier, A. Williams, M.A. Beal, M. Gagné, R. Farmahin, S. Wickramasuriya, A.J.F. Reardon, T. Barton-Maclaren, J.C. Corton, C.L. Yauk, E. Atlas. In vitro transcriptomic analyses reveal pathway perturbations, estrogenic activities, and potencies of data-poor BPA alternative chemicals. Toxicological Sciences 191 (2022) 266-275. https://doi.org/10.1093/toxsci/kfac127 DOI: https://doi.org/10.1093/toxsci/kfac127

[37] C. Stergiopoulos, L.A. Tsakanika, M. Ochsenkühn-Petropoulou, A.T. Kakoulidou, F. Tsopelas. Application of micellar liquid chromatography to model ecotoxicity of pesticides. Comparison with immobilized artificial membrane chromatography and n-octanol-water partitioning. Journal of Chromatography A 1696 (2023) 463951. https://doi.org/10.1016/j.chroma.2023.463951 DOI: https://doi.org/10.1016/j.chroma.2023.463951

[38] C. Stergiopoulos, F. Tsopelas, M. Ochsenkühn-Petropoulou, K. Valko. The use of biomimetic chromatography to predict acute aquatic toxicity of pharmaceutical compounds. Toxicology and Environmental Chemistry 104 (2022) 1-19. https://doi.org/10.1080/02772248.2021.2005065 DOI: https://doi.org/10.1080/02772248.2021.2005065