Abundance of P-glycoprotein and Breast Cancer Resistance Protein Measured by Targeted Proteomics in Human Epileptogenic Brain Tissue

Aniv Mann Brukner; Sarah Billington; Mony Benifla; Tot Bui Nguyen; Hadas Han; Odeya Bennett; Tal Gilboa; Dana Blatch; Yakov Fellig; Olga Volkov; Jashvant D. Unadkat; Dana Ekstein; Sara Eyal

doi:10.1021/acs.molpharmaceut.1c00083

Abundance of P-glycoprotein and Breast Cancer Resistance Protein Measured by Targeted Proteomics in Human Epileptogenic Brain Tissue

Aniv Mann Brukner, Sarah Billington, Mony Benifla, Tot Bui Nguyen, Hadas Han, Odeya Bennett, Tal Gilboa, Dana Blatch, Yakov Fellig, Olga Volkov, Jashvant D. Unadkat, Dana Ekstein, Sara Eyal^*

^*Corresponding author for this work

School of Pharmacy

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Our goal was to measure the absolute differential abundance of key drug transporters in human epileptogenic brain tissue and to compare them between patients and at various distances from the epileptogenic zone within the same patient. Transporter protein abundance was quantified in brain tissue homogenates from patients who underwent epilepsy surgery, using targeted proteomics, and correlations with clinical and tissue characteristics were assessed. Fourteen brain samples (including four epileptogenic hippocampal samples) were collected from nine patients. Among the quantifiable drug transporters, the abundance (median, range) ranked: breast cancer resistance protein (ABCG2/BCRP; 0.55, 0.01-3.26 pmol/g tissue) > P-glycoprotein (ABCB1/MDR1; 0.30, 0.02-1.15 pmol/g tissue) > equilibrative nucleoside transporter 1 (SLC29A1/ENT1; 0.06, 0.001-0.35 pmol/g tissue). The ABCB1/ABCG2 ratio (mean 0.27, range 0.08-0.47) was comparable with literature values from nonepileptogenic brain tissue (mean 0.5-0.8). Transporter abundance was lower in the hippocampi than in the less epileptogenic neocortex of the same patients. ABCG2/BCRP and ABCB1/MDR1 expression strongly correlated with that of glucose transporter 1 (SLC2A1/GLUT1) (r = 0.97, p < 0.001; r = 0.90, p < 0.01, respectively). Low transporter abundance was found in patients with overt vascular pathology, whereas the highest abundance was seen in a sample with normally appearing blood vessels. In conclusion, drug transporter abundance highly varies across patients and between epileptogenic and less epileptogenic brain tissue of the same patient. The strong correlation in abundance of ABCB1/MDR1, ABCG2/BCRP, and SLC2A1/GLUT1 suggests variation in the content of the functional vasculature within the tissue samples. The epileptogenic tissue can be depleted of key drug transport mechanisms, warranting consideration when selecting treatments for patients with drug-resistant epilepsy.

Original language	American English
Pages (from-to)	2263-2273
Number of pages	11
Journal	Molecular Pharmaceutics
Volume	18
Issue number	6
DOIs	https://doi.org/10.1021/acs.molpharmaceut.1c00083
State	Published - 7 Jun 2021

Bibliographical note

Funding Information:
The authors are grateful to the patients who donated their brain samples for research. They appreciate the guidance and assistance of Dr. Eyal Rosenbach, Prof. Simona Ben-Haim, and Prof. Marina Orevi, Division of Nuclear Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. The study was supported by the Prusiner–Abramsky Research Award in Clinical and Basic Neuroscience by the Orion Foundation. Dr. Eyal is affiliated with the David R. Bloom Centre for Pharmacy and Dr. Adolf and Klara Brettler Centre for Research in Molecular Pharmacology and Therapeutics at The Hebrew University of Jerusalem, Israel.

Publisher Copyright:
© 2021 American Chemical Society.

Keywords

P-glycoprotein
antiepileptic drugs
antiseizure medications
breast cancer resistance protein
epilepsy
targeted proteomics

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acs.molpharmaceut.1c00083

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Brukner, A. M., Billington, S., Benifla, M., Nguyen, T. B., Han, H., Bennett, O., Gilboa, T., Blatch, D., Fellig, Y., Volkov, O., Unadkat, J. D., Ekstein, D., & Eyal, S. (2021). Abundance of P-glycoprotein and Breast Cancer Resistance Protein Measured by Targeted Proteomics in Human Epileptogenic Brain Tissue. Molecular Pharmaceutics, 18(6), 2263-2273. https://doi.org/10.1021/acs.molpharmaceut.1c00083

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title = "Abundance of P-glycoprotein and Breast Cancer Resistance Protein Measured by Targeted Proteomics in Human Epileptogenic Brain Tissue",

abstract = "Our goal was to measure the absolute differential abundance of key drug transporters in human epileptogenic brain tissue and to compare them between patients and at various distances from the epileptogenic zone within the same patient. Transporter protein abundance was quantified in brain tissue homogenates from patients who underwent epilepsy surgery, using targeted proteomics, and correlations with clinical and tissue characteristics were assessed. Fourteen brain samples (including four epileptogenic hippocampal samples) were collected from nine patients. Among the quantifiable drug transporters, the abundance (median, range) ranked: breast cancer resistance protein (ABCG2/BCRP; 0.55, 0.01-3.26 pmol/g tissue) > P-glycoprotein (ABCB1/MDR1; 0.30, 0.02-1.15 pmol/g tissue) > equilibrative nucleoside transporter 1 (SLC29A1/ENT1; 0.06, 0.001-0.35 pmol/g tissue). The ABCB1/ABCG2 ratio (mean 0.27, range 0.08-0.47) was comparable with literature values from nonepileptogenic brain tissue (mean 0.5-0.8). Transporter abundance was lower in the hippocampi than in the less epileptogenic neocortex of the same patients. ABCG2/BCRP and ABCB1/MDR1 expression strongly correlated with that of glucose transporter 1 (SLC2A1/GLUT1) (r = 0.97, p < 0.001; r = 0.90, p < 0.01, respectively). Low transporter abundance was found in patients with overt vascular pathology, whereas the highest abundance was seen in a sample with normally appearing blood vessels. In conclusion, drug transporter abundance highly varies across patients and between epileptogenic and less epileptogenic brain tissue of the same patient. The strong correlation in abundance of ABCB1/MDR1, ABCG2/BCRP, and SLC2A1/GLUT1 suggests variation in the content of the functional vasculature within the tissue samples. The epileptogenic tissue can be depleted of key drug transport mechanisms, warranting consideration when selecting treatments for patients with drug-resistant epilepsy.",

keywords = "P-glycoprotein, antiepileptic drugs, antiseizure medications, breast cancer resistance protein, epilepsy, targeted proteomics",

author = "Brukner, {Aniv Mann} and Sarah Billington and Mony Benifla and Nguyen, {Tot Bui} and Hadas Han and Odeya Bennett and Tal Gilboa and Dana Blatch and Yakov Fellig and Olga Volkov and Unadkat, {Jashvant D.} and Dana Ekstein and Sara Eyal",

note = "Funding Information: The authors are grateful to the patients who donated their brain samples for research. They appreciate the guidance and assistance of Dr. Eyal Rosenbach, Prof. Simona Ben-Haim, and Prof. Marina Orevi, Division of Nuclear Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. The study was supported by the Prusiner–Abramsky Research Award in Clinical and Basic Neuroscience by the Orion Foundation. Dr. Eyal is affiliated with the David R. Bloom Centre for Pharmacy and Dr. Adolf and Klara Brettler Centre for Research in Molecular Pharmacology and Therapeutics at The Hebrew University of Jerusalem, Israel. Publisher Copyright: {\textcopyright} 2021 American Chemical Society.",

year = "2021",

month = jun,

day = "7",

doi = "10.1021/acs.molpharmaceut.1c00083",

language = "American English",

volume = "18",

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publisher = "American Chemical Society",

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Brukner, AM, Billington, S, Benifla, M, Nguyen, TB, Han, H, Bennett, O, Gilboa, T, Blatch, D, Fellig, Y, Volkov, O, Unadkat, JD, Ekstein, D & Eyal, S 2021, 'Abundance of P-glycoprotein and Breast Cancer Resistance Protein Measured by Targeted Proteomics in Human Epileptogenic Brain Tissue', Molecular Pharmaceutics, vol. 18, no. 6, pp. 2263-2273. https://doi.org/10.1021/acs.molpharmaceut.1c00083

TY - JOUR

T1 - Abundance of P-glycoprotein and Breast Cancer Resistance Protein Measured by Targeted Proteomics in Human Epileptogenic Brain Tissue

AU - Brukner, Aniv Mann

AU - Billington, Sarah

AU - Benifla, Mony

AU - Nguyen, Tot Bui

AU - Han, Hadas

AU - Bennett, Odeya

AU - Gilboa, Tal

AU - Blatch, Dana

AU - Fellig, Yakov

AU - Volkov, Olga

AU - Unadkat, Jashvant D.

AU - Ekstein, Dana

AU - Eyal, Sara

N1 - Funding Information: The authors are grateful to the patients who donated their brain samples for research. They appreciate the guidance and assistance of Dr. Eyal Rosenbach, Prof. Simona Ben-Haim, and Prof. Marina Orevi, Division of Nuclear Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. The study was supported by the Prusiner–Abramsky Research Award in Clinical and Basic Neuroscience by the Orion Foundation. Dr. Eyal is affiliated with the David R. Bloom Centre for Pharmacy and Dr. Adolf and Klara Brettler Centre for Research in Molecular Pharmacology and Therapeutics at The Hebrew University of Jerusalem, Israel. Publisher Copyright: © 2021 American Chemical Society.

PY - 2021/6/7

Y1 - 2021/6/7

N2 - Our goal was to measure the absolute differential abundance of key drug transporters in human epileptogenic brain tissue and to compare them between patients and at various distances from the epileptogenic zone within the same patient. Transporter protein abundance was quantified in brain tissue homogenates from patients who underwent epilepsy surgery, using targeted proteomics, and correlations with clinical and tissue characteristics were assessed. Fourteen brain samples (including four epileptogenic hippocampal samples) were collected from nine patients. Among the quantifiable drug transporters, the abundance (median, range) ranked: breast cancer resistance protein (ABCG2/BCRP; 0.55, 0.01-3.26 pmol/g tissue) > P-glycoprotein (ABCB1/MDR1; 0.30, 0.02-1.15 pmol/g tissue) > equilibrative nucleoside transporter 1 (SLC29A1/ENT1; 0.06, 0.001-0.35 pmol/g tissue). The ABCB1/ABCG2 ratio (mean 0.27, range 0.08-0.47) was comparable with literature values from nonepileptogenic brain tissue (mean 0.5-0.8). Transporter abundance was lower in the hippocampi than in the less epileptogenic neocortex of the same patients. ABCG2/BCRP and ABCB1/MDR1 expression strongly correlated with that of glucose transporter 1 (SLC2A1/GLUT1) (r = 0.97, p < 0.001; r = 0.90, p < 0.01, respectively). Low transporter abundance was found in patients with overt vascular pathology, whereas the highest abundance was seen in a sample with normally appearing blood vessels. In conclusion, drug transporter abundance highly varies across patients and between epileptogenic and less epileptogenic brain tissue of the same patient. The strong correlation in abundance of ABCB1/MDR1, ABCG2/BCRP, and SLC2A1/GLUT1 suggests variation in the content of the functional vasculature within the tissue samples. The epileptogenic tissue can be depleted of key drug transport mechanisms, warranting consideration when selecting treatments for patients with drug-resistant epilepsy.

AB - Our goal was to measure the absolute differential abundance of key drug transporters in human epileptogenic brain tissue and to compare them between patients and at various distances from the epileptogenic zone within the same patient. Transporter protein abundance was quantified in brain tissue homogenates from patients who underwent epilepsy surgery, using targeted proteomics, and correlations with clinical and tissue characteristics were assessed. Fourteen brain samples (including four epileptogenic hippocampal samples) were collected from nine patients. Among the quantifiable drug transporters, the abundance (median, range) ranked: breast cancer resistance protein (ABCG2/BCRP; 0.55, 0.01-3.26 pmol/g tissue) > P-glycoprotein (ABCB1/MDR1; 0.30, 0.02-1.15 pmol/g tissue) > equilibrative nucleoside transporter 1 (SLC29A1/ENT1; 0.06, 0.001-0.35 pmol/g tissue). The ABCB1/ABCG2 ratio (mean 0.27, range 0.08-0.47) was comparable with literature values from nonepileptogenic brain tissue (mean 0.5-0.8). Transporter abundance was lower in the hippocampi than in the less epileptogenic neocortex of the same patients. ABCG2/BCRP and ABCB1/MDR1 expression strongly correlated with that of glucose transporter 1 (SLC2A1/GLUT1) (r = 0.97, p < 0.001; r = 0.90, p < 0.01, respectively). Low transporter abundance was found in patients with overt vascular pathology, whereas the highest abundance was seen in a sample with normally appearing blood vessels. In conclusion, drug transporter abundance highly varies across patients and between epileptogenic and less epileptogenic brain tissue of the same patient. The strong correlation in abundance of ABCB1/MDR1, ABCG2/BCRP, and SLC2A1/GLUT1 suggests variation in the content of the functional vasculature within the tissue samples. The epileptogenic tissue can be depleted of key drug transport mechanisms, warranting consideration when selecting treatments for patients with drug-resistant epilepsy.

KW - P-glycoprotein

KW - antiepileptic drugs

KW - antiseizure medications

KW - breast cancer resistance protein

KW - epilepsy

KW - targeted proteomics

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Abundance of P-glycoprotein and Breast Cancer Resistance Protein Measured by Targeted Proteomics in Human Epileptogenic Brain Tissue

Abstract

Bibliographical note

Keywords

UN SDGs

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