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Title: Breast cancer resistance protein (BCRP) at the blood-brain barrier and its interactions with steroidal compounds
Author: Cooray, H. C.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2005
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Five different plant polyphenols (resveratrol, hesperetin, quercetin, daidzein and silymarin) were shown to interact with BCRP expressed in MCF7/MR and K562/BCRP cells, significantly increasing the accumulation of mitoxantrone and bodipy prazosin above control levels. They also stimulated the BCRP-associated ATPase activity in vesicles derived from Lactococcus lactis bacteria transformed with BCRP cDNA. None of these polyphenols had any effects on the long-term expression of BCRP in MCF7/MR cells. Inhaled corticosteroids have revolutionized the treatment of chronic obstructive pulmonary disease but cause long term suppression of the hypothalamic-pituitary-adrenal (HPA) axis, leading to low cortisol levels. It has been suggested that P-gp at the BBB may influence suppression of the HPA by oral corticosteroids. Five inhaled corticosteroids were tested for their ability to modulate P-gp and BCRP function. Beclomethasone dipropionate, mometasone furoate and the newer ciclesonide used at 5 and 10 μM increased the accumulation of mitoxantrone in BCRP-expressing MCF7/MR cells, and the accumulation of calcein in P-gp expressing SW620/R cells, though triamcinolone acetonide and budesonide had no inhibitory effects. Beclomethasone, mometasone and ciclesonide at 5 μM enhanced the cytotoxicity of doxorubicin in SW620/R cells. These three compounds as well as budesonide stimulated the BCRP-associated ATPase activity in L. lactis vesicles expressing BCRP. Both the plant polyphenols and the three corticosteroids examined in this study could either be ‘fast diffusing’ or competitive substrates of BCRP, inhibiting the efflux of another substrate while stimulating the BCRP-associated ATPase activity. These results establish that BCRP is present at the BBB and may modulate the access of both dietary and therapeutic steroidal compounds into the brain.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available