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
N1 - Funding Information:
Acknowledgements. We thank Dr. J. Kandimalla for assistance with animal surgery, and our late colleague, Dr. Menes Afriyie, for image analysis. The work was supported in part by NIH grants RO1 DK46952, P30 DK41296, P30 CA13330, and MO1 RR12248, and by grant 3894 from the Long Island Jewish Medical Center.
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
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U2 - 10.1007/s00259-002-1111-z
DO - 10.1007/s00259-002-1111-z
M3 - Article
C2 - 12536246
AN - SCOPUS:0041691354
SN - 1619-7070
VL - 30
SP - 1024
EP - 1031
JO - European Journal of Nuclear Medicine and Molecular Imaging
JF - European Journal of Nuclear Medicine and Molecular Imaging
IS - 7
ER -