Increasing BMI is associated with reduced expression of P-glycoprotein (ABCB1 gene) in the human brain with a stronger association in African Americans than Caucasians

Vendelbo, J; Olesen, Rasmus H.; Lauridsen, Jesper Krogh; Rungby, Jørgen; Kleinman, Joel E.; Hyde, Thomas M.

doi:10.1038/tpj.2016.74

Cited by 14 publications

(10 citation statements)

References 45 publications

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“…The inter-individual variability of Pgp expression is moreover high and depends on diverse factors including gender (82), ethnicity, age, and body mass index (BMI) (83). The Pgp expression level can additionally vary as a function of time with X-ray irradiation (84), ultra violet light irradiation (85), heat shock (86), and importantly, with diet, medication, metabolism and disease state (as discussed below).…”

Section: Pgp In Absorption and Excretionmentioning

confidence: 99%

P-Glycoprotein: One Mechanism, Many Tasks and the Consequences for Pharmacotherapy of Cancers

Seelig

2020

Front. Oncol.

122

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P-glycoprotein or multidrug resistance protein (MDR1) is an adenosine triphosphate (ATP) binding cassette transporter (ABCB1) intensely investigated because it is an obstacle to successful pharmacotherapy of cancers. P-glycoprotein prevents cellular uptake of a large number of structurally and functionally diverse compounds, including most cancer therapeutics and in this way causes multidrug resistance (MDR). To overcome MDR, and thus improve cancer treatment, an understanding of P-glycoprotein inhibition at the molecular level is required. With this goal in mind, we propose rules that predict whether a compound is a modulator, substrate, inhibitor, or inducer of P-glycoprotein. This new set of rules is derived from a quantitative analysis of the drug binding and transport properties of P-glycoprotein. We further discuss the role of P-glycoprotein in immune surveillance and cell metabolism. Finally, the predictive power of the proposed rules is demonstrated with a set of FDA approved drugs which have been repurposed for cancer therapy.

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Section: Pgp In Absorption and Excretionmentioning

confidence: 99%

P-Glycoprotein: One Mechanism, Many Tasks and the Consequences for Pharmacotherapy of Cancers

Seelig

2020

Front. Oncol.

122

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“…found body mass index is negatively associated with expression of ABCB1 (the gene encoding P-gp) in the frontal cortex (113). It is interesting that although mRNA levels in human brain decrease with increased body mass index (113), protein levels of P-gp do not change at the BBB, at least in HFD-fed obese mice (21). Whether or not P-gp protein and/or function is altered at the BBB in humans remains to be determined.…”

Section: Bbb Transport and Transporter Changes In Obesitymentioning

confidence: 99%

Blood-Brain Barriers in Obesity

Rhea

Salameh

Logsdon

et al. 2017

AAPS J

107

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After decades of rapid increase, the rate of obesity in adults in the USA is beginning to slow and the rate of childhood obesity is stabilizing. Despite these improvements, the obesity epidemic continues to be a major health and financial burden. Obesity is associated with serious negative health outcomes such as cardiovascular disease, type II diabetes, and, more recently, cognitive decline and various neurodegenerative dementias such as Alzheimer’s disease. In the past decade, major advancements have contributed to the understanding of the role of the central nervous system (CNS) in the development of obesity and how peripheral hormonal signals modulate CNS regulation of energy homeostasis. In this article, we address how obesity affects the structure and function of the blood-brain barrier (BBB), the impact of obesity on Alzheimer’s disease, the effects of obesity on circulating proteins and their transport into the brain, and how these changes can potentially be reversed by weight loss.

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“…Although we did not observe any effect of body mass index on the V T of [ 18 F]MC225 in our small sample, increased body mass index is associated with reduced expression of P-gp in the human brain [48]. Interestingly, low-density lipoprotein receptor-related 1 and P-gp are altered in diabetes mellitus (DM) [49].…”

Section: Discussionmentioning

confidence: 55%

First clinical assessment of [18F]MC225, a novel fluorine-18 labelled PET tracer for measuring functional P-glycoprotein at the blood–brain barrier

et al. 2021

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Objective 5-(1-(2-[ 18 F]fluoroethoxy))- [3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-5,6,7,8-tetrahydronaphthalen ([ 18 F]MC225) is a selective substrate for P-glycoprotein (P-gp), possessing suitable properties for measuring overexpression of P-gp in the brain. This is the first-in-human study to examine safety, radiation dosimetry and P-gp function at the blood-brain barrier (BBB) of [ 18 F]MC225 in healthy subjects. Methods [ 18 F]MC225 biodistribution and dosimetry were determined in 3 healthy male subjects, using serial 2 h and intermittent 4 and 6 h whole-body PET scans acquired after [ 18 F]MC225 injection. Dynamic [ 18 F]MC225 brain PET (90 min) was obtained in 5 healthy male subjects. Arterial blood was sampled at various time intervals during scanning and the fraction of unchanged [ 18 F]MC225 in plasma was determined. T1-weighted MRI was performed for anatomical coregistration. Total distribution volume (V T ) was estimated using 1-and 2-tissue-compartment models (1-TCM and 2-TCM, respectively). V T was also estimated using the Logan graphical method (Logan plot) (t* = 20 min). Surrogate parameters without blood sampling (area-under the curve [AUC] of regional time-activity curves [TACs] and negative slope of calculated TACs) were compared with the V T values. ResultsNo serious adverse events occurred throughout the study period. Although biodistribution implied hepatobiliary excretion, secretion of radioactivity from liver to small intestine through the gallbladder was very slow. Total renal excreted radioactivity recovered during 6 h after injection was < 2%ID. Absorbed dose was the highest in the pancreas (mean ± SD, 203 ± 45 μGy/MBq) followed by the liver (83 ± 11 μGy/MBq). Mean effective dose with and without urination was 17 ± 1 μSv/MBq. [ 18 F]MC225 readily entered the brain, distributing homogeneously in grey matter regions. 2-TCM provided lower Akaike information criterion scores than did 1-TCM. V T estimated by Logan plot was well correlated with that of 2-TCM (r 2 > 0.9). AUCs of TACs were positively correlated with V T (2-TCM) values (r 2 : AUC 0-60 min = 0.61, AUC 0-30 min = 0.62, AUC 30-60 min = 0.59, p < 0.0001). Negative slope of SUV TACs was negatively correlated with V T (2-TCM) values (r 2 = 0.53, p < 0.0001). Conclusions This initial evaluation indicated that [ 18 F]MC225 is a suitable and safe PET tracer for measuring P-gp function at the BBB.

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Increasing BMI is associated with reduced expression of P-glycoprotein (ABCB1 gene) in the human brain with a stronger association in African Americans than Caucasians

Cited by 14 publications

References 45 publications

P-Glycoprotein: One Mechanism, Many Tasks and the Consequences for Pharmacotherapy of Cancers

P-Glycoprotein: One Mechanism, Many Tasks and the Consequences for Pharmacotherapy of Cancers

Blood-Brain Barriers in Obesity

First clinical assessment of [18F]MC225, a novel fluorine-18 labelled PET tracer for measuring functional P-glycoprotein at the blood–brain barrier

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