Sestamibi is a substrate for MDR1 and MDR2 P-glycoprotein genes

Brigid Joseph, Kuldeep K. Bhargava, Harmeet Malhi, Michael L. Schilsky, Diwakar Jain, Christopher J. Palestro, Sanjeev Gupta

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Technetium-99m sestamibi has attracted interest for assessment of the function of P-glycoproteins, which are well expressed in the liver and have roles in biliary transport and the removal of chemotherapeutic drugs. To further examine the cross-reactivity of 99mTc-sestamibi for P-glycoprotein family members, we conducted studies in animals. Hepatobiliary secretion of 99mTc-sestamibi was determined in normal FVB/N mice, mutant mice with specific P-glycoprotein deficiencies in the FVB/N background, normal Long-Evans Agouti (LEA) rats, and Long-Evans Cinnamon (LEC) rats with abnormal copper transport and liver disease but intact P-glycoprotein expression. After intrasplenic injection, 99mTc-sestamibi was rapidly incorporated in the mouse and rat liver, with maximal accumulation after 102±31 and 109±16 s, respectively (P=NS). In normal mice and rats, 55%±11% and 55%±6%, respectively, of the maximal sestamibi activity was retained in the liver after 1 h (P=NS). In double knockout mice lacking both mdr1a and mdr1b homologs of the human MDR1 (ABCB1) gene, 88%±11% of maximal sestamibi activity was retained in the liver after 1 h (P<0.001). In knockout mice deficient in either mdr1a gene or mdr2 (ABCB4) gene, biliary sestamibi excretion was also impaired, although this impairment was relatively less pronounced in ABCB4-deficient mice than in double knockout mice lacking both ABCB1 gene homologs (P<0.03). Hepatobiliary sestamibi excretion in LEC rats was not different from that in control normal rats, despite the presence of significant liver disease in the former. Hepatobiliary sestamibi excretion requires P-glycoproteins and is unperturbed in chronic liver disease. Sestamibi appears to be a substrate for both ABCB1 and ABCB4 genes, although the former utilizes it far more efficiently. Assessment of P-glycoprotein activity with sestamibi should consider how regulation of ABCB1 and related family members might modulate sestamibi incorporation.

Original languageEnglish (US)
Pages (from-to)1024-1031
Number of pages8
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume30
Issue number7
DOIs
StatePublished - Jul 1 2003

Fingerprint

P-Glycoprotein
Technetium Tc 99m Sestamibi
Inbred LEC Rats
Knockout Mice
P-Glycoproteins
Liver Diseases
Genes
Liver
Menkes Kinky Hair Syndrome
Long Evans Rats
Chronic Disease
Injections
Pharmaceutical Preparations
Hepatobiliary Elimination

Keywords

  • ABCB1 gene
  • ABCB4 gene
  • Liver
  • Mdr1 gene
  • Mdr2 gene
  • P-glycoprotein
  • Sestamibi

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Radiological and Ultrasound Technology

Cite this

Sestamibi is a substrate for MDR1 and MDR2 P-glycoprotein genes. / Joseph, Brigid; Bhargava, Kuldeep K.; Malhi, Harmeet; Schilsky, Michael L.; Jain, Diwakar; Palestro, Christopher J.; Gupta, Sanjeev.

In: European Journal of Nuclear Medicine and Molecular Imaging, Vol. 30, No. 7, 01.07.2003, p. 1024-1031.

Research output: Contribution to journalArticle

Joseph, Brigid ; Bhargava, Kuldeep K. ; Malhi, Harmeet ; Schilsky, Michael L. ; Jain, Diwakar ; Palestro, Christopher J. ; Gupta, Sanjeev. / Sestamibi is a substrate for MDR1 and MDR2 P-glycoprotein genes. In: European Journal of Nuclear Medicine and Molecular Imaging. 2003 ; Vol. 30, No. 7. pp. 1024-1031.
@article{293653c494d34f95b2dc30bd5d84616b,
title = "Sestamibi is a substrate for MDR1 and MDR2 P-glycoprotein genes",
abstract = "Technetium-99m sestamibi has attracted interest for assessment of the function of P-glycoproteins, which are well expressed in the liver and have roles in biliary transport and the removal of chemotherapeutic drugs. To further examine the cross-reactivity of 99mTc-sestamibi for P-glycoprotein family members, we conducted studies in animals. Hepatobiliary secretion of 99mTc-sestamibi was determined in normal FVB/N mice, mutant mice with specific P-glycoprotein deficiencies in the FVB/N background, normal Long-Evans Agouti (LEA) rats, and Long-Evans Cinnamon (LEC) rats with abnormal copper transport and liver disease but intact P-glycoprotein expression. After intrasplenic injection, 99mTc-sestamibi was rapidly incorporated in the mouse and rat liver, with maximal accumulation after 102±31 and 109±16 s, respectively (P=NS). In normal mice and rats, 55{\%}±11{\%} and 55{\%}±6{\%}, respectively, of the maximal sestamibi activity was retained in the liver after 1 h (P=NS). In double knockout mice lacking both mdr1a and mdr1b homologs of the human MDR1 (ABCB1) gene, 88{\%}±11{\%} of maximal sestamibi activity was retained in the liver after 1 h (P<0.001). In knockout mice deficient in either mdr1a gene or mdr2 (ABCB4) gene, biliary sestamibi excretion was also impaired, although this impairment was relatively less pronounced in ABCB4-deficient mice than in double knockout mice lacking both ABCB1 gene homologs (P<0.03). Hepatobiliary sestamibi excretion in LEC rats was not different from that in control normal rats, despite the presence of significant liver disease in the former. Hepatobiliary sestamibi excretion requires P-glycoproteins and is unperturbed in chronic liver disease. Sestamibi appears to be a substrate for both ABCB1 and ABCB4 genes, although the former utilizes it far more efficiently. Assessment of P-glycoprotein activity with sestamibi should consider how regulation of ABCB1 and related family members might modulate sestamibi incorporation.",
keywords = "ABCB1 gene, ABCB4 gene, Liver, Mdr1 gene, Mdr2 gene, P-glycoprotein, Sestamibi",
author = "Brigid Joseph and Bhargava, {Kuldeep K.} and Harmeet Malhi and Schilsky, {Michael L.} and Diwakar Jain and Palestro, {Christopher J.} and Sanjeev Gupta",
year = "2003",
month = "7",
day = "1",
doi = "10.1007/s00259-002-1111-z",
language = "English (US)",
volume = "30",
pages = "1024--1031",
journal = "European Journal of Nuclear Medicine and Molecular Imaging",
issn = "1619-7070",
publisher = "Springer Verlag",
number = "7",

}

TY - JOUR

T1 - Sestamibi is a substrate for MDR1 and MDR2 P-glycoprotein genes

AU - Joseph, Brigid

AU - Bhargava, Kuldeep K.

AU - Malhi, Harmeet

AU - Schilsky, Michael L.

AU - Jain, Diwakar

AU - Palestro, Christopher J.

AU - Gupta, Sanjeev

PY - 2003/7/1

Y1 - 2003/7/1

N2 - Technetium-99m sestamibi has attracted interest for assessment of the function of P-glycoproteins, which are well expressed in the liver and have roles in biliary transport and the removal of chemotherapeutic drugs. To further examine the cross-reactivity of 99mTc-sestamibi for P-glycoprotein family members, we conducted studies in animals. Hepatobiliary secretion of 99mTc-sestamibi was determined in normal FVB/N mice, mutant mice with specific P-glycoprotein deficiencies in the FVB/N background, normal Long-Evans Agouti (LEA) rats, and Long-Evans Cinnamon (LEC) rats with abnormal copper transport and liver disease but intact P-glycoprotein expression. After intrasplenic injection, 99mTc-sestamibi was rapidly incorporated in the mouse and rat liver, with maximal accumulation after 102±31 and 109±16 s, respectively (P=NS). In normal mice and rats, 55%±11% and 55%±6%, respectively, of the maximal sestamibi activity was retained in the liver after 1 h (P=NS). In double knockout mice lacking both mdr1a and mdr1b homologs of the human MDR1 (ABCB1) gene, 88%±11% of maximal sestamibi activity was retained in the liver after 1 h (P<0.001). In knockout mice deficient in either mdr1a gene or mdr2 (ABCB4) gene, biliary sestamibi excretion was also impaired, although this impairment was relatively less pronounced in ABCB4-deficient mice than in double knockout mice lacking both ABCB1 gene homologs (P<0.03). Hepatobiliary sestamibi excretion in LEC rats was not different from that in control normal rats, despite the presence of significant liver disease in the former. Hepatobiliary sestamibi excretion requires P-glycoproteins and is unperturbed in chronic liver disease. Sestamibi appears to be a substrate for both ABCB1 and ABCB4 genes, although the former utilizes it far more efficiently. Assessment of P-glycoprotein activity with sestamibi should consider how regulation of ABCB1 and related family members might modulate sestamibi incorporation.

AB - Technetium-99m sestamibi has attracted interest for assessment of the function of P-glycoproteins, which are well expressed in the liver and have roles in biliary transport and the removal of chemotherapeutic drugs. To further examine the cross-reactivity of 99mTc-sestamibi for P-glycoprotein family members, we conducted studies in animals. Hepatobiliary secretion of 99mTc-sestamibi was determined in normal FVB/N mice, mutant mice with specific P-glycoprotein deficiencies in the FVB/N background, normal Long-Evans Agouti (LEA) rats, and Long-Evans Cinnamon (LEC) rats with abnormal copper transport and liver disease but intact P-glycoprotein expression. After intrasplenic injection, 99mTc-sestamibi was rapidly incorporated in the mouse and rat liver, with maximal accumulation after 102±31 and 109±16 s, respectively (P=NS). In normal mice and rats, 55%±11% and 55%±6%, respectively, of the maximal sestamibi activity was retained in the liver after 1 h (P=NS). In double knockout mice lacking both mdr1a and mdr1b homologs of the human MDR1 (ABCB1) gene, 88%±11% of maximal sestamibi activity was retained in the liver after 1 h (P<0.001). In knockout mice deficient in either mdr1a gene or mdr2 (ABCB4) gene, biliary sestamibi excretion was also impaired, although this impairment was relatively less pronounced in ABCB4-deficient mice than in double knockout mice lacking both ABCB1 gene homologs (P<0.03). Hepatobiliary sestamibi excretion in LEC rats was not different from that in control normal rats, despite the presence of significant liver disease in the former. Hepatobiliary sestamibi excretion requires P-glycoproteins and is unperturbed in chronic liver disease. Sestamibi appears to be a substrate for both ABCB1 and ABCB4 genes, although the former utilizes it far more efficiently. Assessment of P-glycoprotein activity with sestamibi should consider how regulation of ABCB1 and related family members might modulate sestamibi incorporation.

KW - ABCB1 gene

KW - ABCB4 gene

KW - Liver

KW - Mdr1 gene

KW - Mdr2 gene

KW - P-glycoprotein

KW - Sestamibi

UR - http://www.scopus.com/inward/record.url?scp=0041691354&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0041691354&partnerID=8YFLogxK

U2 - 10.1007/s00259-002-1111-z

DO - 10.1007/s00259-002-1111-z

M3 - Article

C2 - 12536246

AN - SCOPUS:0041691354

VL - 30

SP - 1024

EP - 1031

JO - European Journal of Nuclear Medicine and Molecular Imaging

JF - European Journal of Nuclear Medicine and Molecular Imaging

SN - 1619-7070

IS - 7

ER -