Impact of Plastic-Related Compounds on P-Glycoprotein and Breast Cancer Resistance Protein In Vitro

Publication type:
Journal article
Metadata:
Autoren
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000959843200001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.3390/molecules28062710
eISSN
1420-3049
Externe Identifier
  • Clarivate Analytics Document Solution ID: C1UE1
  • PubMed Identifier: 36985682
Ausgabe der Veröffentlichung
6
Zeitschrift
MOLECULES
Schlüsselwörter
  • plastic
  • microplastic
  • cytotoxicity
  • uptake
  • live cell imaging
  • microscopy
Artikelnummer
ARTN 2710
Datum der Veröffentlichung
2023
Status
Published
Titel
Impact of Plastic-Related Compounds on P-Glycoprotein and Breast Cancer Resistance Protein In Vitro
Sub types
  • Article
Ausgabe der Zeitschrift
28

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
<jats:p>Plastic in oceans degrades to microplastics and nanoplastics, causing various problems for marine fauna and flora. Recently, microplastic has been detected in blood, breast milk and placenta, underlining their ability to enter the human body with still unknown effects. In addition, plastic contains other compounds such as plasticizers, antioxidants or lubricants, whose impact on human health is also elusive. On the cellular level, two transporters involved in cell protection and detoxification of xenobiotic compounds are the ABC-transporters P-glycoprotein (P-gp, MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2). Despite the great importance of these proteins to maintain the correct cellular balance, their interaction with plastic and related products is evasive. In this study, the possible interaction between different plastic-related compounds and these two transporters was investigated. Applying virtual compound screening and molecular docking of more than 1000 commercially available plastic compounds, we identified candidates most probably interacting with these two transporters. Cytotoxicity and uptake assays confirmed their toxic interaction on P-glycoprotein-overexpressing CEM/ADR5000 and BCRP-overexpressing MDA-MD-231-BCRP cell lines. To specifically visualize the results obtained on the P-glycoprotein inhibitor 2,2’-methylenebis(6-tert-butyl-4-methylphenol), we performed live cell time-lapse microscopy. Confocal fluorescence microscopy was used to understand the behavior of the molecule and the consequences that it has on the uptake of the well-known substrate doxorubicin and, in comparison, with the known inhibitor verapamil. Based on the results, we provide evidence that the compound in question is an inhibitor of the P-glycoprotein. Moreover, it is also possible that 2,2’-methylenebis(6-tert-butyl-4-methylphenol), together with three other compounds, may also inhibit the breast cancer resistance protein. This discovery implies that plastic-related compounds can not only harm the human body but can also inhibit detoxifying efflux pumps, which increases their toxic potential as these transporters lose their physiological functions.</jats:p>
Autoren
DOI
10.3390/molecules28062710
eISSN
1420-3049
Ausgabe der Veröffentlichung
6
Zeitschrift
Molecules
Sprache
en
Online publication date
2023
Paginierung
2710 - 2710
Status
Published online
Herausgeber
MDPI AG
Herausgeber URL
http://dx.doi.org/10.3390/molecules28062710
Datum der Datenerfassung
2023
Titel
Impact of Plastic-Related Compounds on P-Glycoprotein and Breast Cancer Resistance Protein In Vitro
Ausgabe der Zeitschrift
28

Data source: Crossref

Abstract
Plastic in oceans degrades to microplastics and nanoplastics, causing various problems for marine fauna and flora. Recently, microplastic has been detected in blood, breast milk and placenta, underlining their ability to enter the human body with still unknown effects. In addition, plastic contains other compounds such as plasticizers, antioxidants or lubricants, whose impact on human health is also elusive. On the cellular level, two transporters involved in cell protection and detoxification of xenobiotic compounds are the ABC-transporters P-glycoprotein (P-gp, MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2). Despite the great importance of these proteins to maintain the correct cellular balance, their interaction with plastic and related products is evasive. In this study, the possible interaction between different plastic-related compounds and these two transporters was investigated. Applying virtual compound screening and molecular docking of more than 1000 commercially available plastic compounds, we identified candidates most probably interacting with these two transporters. Cytotoxicity and uptake assays confirmed their toxic interaction on P-glycoprotein-overexpressing CEM/ADR5000 and BCRP-overexpressing MDA-MD-231-BCRP cell lines. To specifically visualize the results obtained on the P-glycoprotein inhibitor 2,2'-methylenebis(6-tert-butyl-4-methylphenol), we performed live cell time-lapse microscopy. Confocal fluorescence microscopy was used to understand the behavior of the molecule and the consequences that it has on the uptake of the well-known substrate doxorubicin and, in comparison, with the known inhibitor verapamil. Based on the results, we provide evidence that the compound in question is an inhibitor of the P-glycoprotein. Moreover, it is also possible that 2,2'-methylenebis(6-tert-butyl-4-methylphenol), together with three other compounds, may also inhibit the breast cancer resistance protein. This discovery implies that plastic-related compounds can not only harm the human body but can also inhibit detoxifying efflux pumps, which increases their toxic potential as these transporters lose their physiological functions.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Autoren
DOI
10.3390/molecules28062710
eISSN
1420-3049
Externe Identifier
  • PubMed Identifier: 36985682
  • PubMed Central ID: PMC10058098
Funding acknowledgements
  • Deutsche Forschungsgemeinschaft: 497669232
  • Deutsche Forschungsgemeinschaft: GRK 2015/2
  • Deutsche Forschungsgemeinschaft: project number 497669232
Open access
true
ISSN
1420-3049
Ausgabe der Veröffentlichung
6
Zeitschrift
Molecules (Basel, Switzerland)
Schlüsselwörter
  • Humans
  • Breast Neoplasms
  • Plastics
  • Neoplasm Proteins
  • Female
  • Molecular Docking Simulation
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
Sprache
eng
Medium
Electronic
Online publication date
2023
Open access status
Open Access
Paginierung
2710
Datum der Veröffentlichung
2023
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2023
Titel
Impact of Plastic-Related Compounds on P-Glycoprotein and Breast Cancer Resistance Protein In Vitro.
Sub types
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
28

Files

https://www.mdpi.com/1420-3049/28/6/2710/pdf?version=1679027598 https://europepmc.org/articles/PMC10058098?pdf=render

Data source: Europe PubMed Central

Abstract
Plastic in oceans degrades to microplastics and nanoplastics, causing various problems for marine fauna and flora. Recently, microplastic has been detected in blood, breast milk and placenta, underlining their ability to enter the human body with still unknown effects. In addition, plastic contains other compounds such as plasticizers, antioxidants or lubricants, whose impact on human health is also elusive. On the cellular level, two transporters involved in cell protection and detoxification of xenobiotic compounds are the ABC-transporters P-glycoprotein (P-gp, MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2). Despite the great importance of these proteins to maintain the correct cellular balance, their interaction with plastic and related products is evasive. In this study, the possible interaction between different plastic-related compounds and these two transporters was investigated. Applying virtual compound screening and molecular docking of more than 1000 commercially available plastic compounds, we identified candidates most probably interacting with these two transporters. Cytotoxicity and uptake assays confirmed their toxic interaction on P-glycoprotein-overexpressing CEM/ADR5000 and BCRP-overexpressing MDA-MD-231-BCRP cell lines. To specifically visualize the results obtained on the P-glycoprotein inhibitor 2,2'-methylenebis(6-tert-butyl-4-methylphenol), we performed live cell time-lapse microscopy. Confocal fluorescence microscopy was used to understand the behavior of the molecule and the consequences that it has on the uptake of the well-known substrate doxorubicin and, in comparison, with the known inhibitor verapamil. Based on the results, we provide evidence that the compound in question is an inhibitor of the P-glycoprotein. Moreover, it is also possible that 2,2'-methylenebis(6-tert-butyl-4-methylphenol), together with three other compounds, may also inhibit the breast cancer resistance protein. This discovery implies that plastic-related compounds can not only harm the human body but can also inhibit detoxifying efflux pumps, which increases their toxic potential as these transporters lose their physiological functions.
Date of acceptance
2023
Autoren
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/36985682
DOI
10.3390/molecules28062710
eISSN
1420-3049
Externe Identifier
  • PubMed Central ID: PMC10058098
Funding acknowledgements
  • Deutsche Forschungsgemeinschaft: GRK 2015/2
  • Deutsche Forschungsgemeinschaft: project number 497669232
Ausgabe der Veröffentlichung
6
Zeitschrift
Molecules
Schlüsselwörter
  • cytotoxicity
  • live cell imaging
  • microplastic
  • microscopy
  • plastic
  • uptake
  • Humans
  • Female
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Plastics
  • Molecular Docking Simulation
  • Neoplasm Proteins
  • ATP Binding Cassette Transporter, Subfamily B
  • Breast Neoplasms
Sprache
eng
Country
Switzerland
PII
molecules28062710
Datum der Veröffentlichung
2023
Status
Published online
Datum, an dem der Datensatz öffentlich gemacht wurde
2023
Titel
Impact of Plastic-Related Compounds on P-Glycoprotein and Breast Cancer Resistance Protein In Vitro.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
28

Data source: PubMed

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