A revised role for P-glycoprotein in the brain distribution of dexamethasone, cortisol, and corticosterone in wild-type and ABCB1A/B-deficient mice

被引:47
作者
Mason, Brittany L. [1 ,2 ]
Pariante, Carmine M. [1 ]
Thomas, Sarah A. [2 ]
机构
[1] Kings Coll London, Inst Psychiat, Sect & Lab Stress Psychiat & Immunol, London SE5 9NU, England
[2] Kings Coll London, Pharmaceut Sci Res Div, London SE5 9NU, England
基金
英国医学研究理事会; 英国惠康基金;
关键词
D O I
10.1210/en.2008-0041
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The ABCB1-type multidrug resistance efflux transporter P-glycoprotein (P-gp) has been hypothesized to regulate hypothalamic-pituitary-adrenal axis activity by limiting the access of glucocorticoids to the brain. In vivo systemic administration studies using P-gp-deficient mice have shown increased glucocorticoid entry to the brain compared with wild-type controls. However, these studies did not control for the presence of radiolabeled drug in the capillaries, verify an intact blood-brain barrier, or confirm stability of the glucocorticoids used. In the present study, an in situ brain perfusion method, coupled with capillary depletion and HPLC analyses, was used to quantify brain uptake of [H-3] dexamethasone, [H-3] cortisol, and [H-3] corticosterone in P-gp-deficient and control mice. A vascular marker was included in these experiments. The results show that brain uptake of [H-3] dexamethasone was increased in the frontal cortex, hippocampus, hypothalamus, and cerebellum of P-gp-deficient mice compared with wild-type controls. Brain uptake of [H-3] cortisol was increased in the hypothalamus of P-gp-deficient mice compared with wild-type controls, but no differences were detected in other regions. Brain uptake of [H-3] corticosterone was not increased in P-gp-deficient mice compared with wild-type controls in any brain areas. After our systemic administration of the same radiolabeled glucocorticoids, HPLC analysis of plasma samples identified additional radiolabeled components, likely to be metabolites. This could explain previous findings from systemic administration studies, showing an effect of P-gp not only for dexamethasone and cortisol, but also for corticosterone. This in situ study highlights the different affinities of dexamethasone, cortisol, and corticosterone for P-gp, and suggests that the entry of the endogenous glucocorticoids into the mouse brain is not tightly regulated by P-gp. Therefore, our current understanding of the role of P-gp in hypothalamic-pituitary-adrenal regulation in mice requires revision.
引用
收藏
页码:5244 / 5253
页数:10
相关论文
共 37 条
[1]  
ALTUVIA S, 1993, J BIOL CHEM, V268, P27127
[2]   COMPARISONS OF P-GLYCOPROTEIN EXPRESSION IN ISOLATED RAT-BRAIN MICROVESSELS AND IN PRIMARY CULTURES OF ENDOTHELIAL-CELLS DERIVED FROM MICROVASCULATURE OF RAT-BRAIN, EPIDIDYMAL FAT PAD AND FROM AORTA [J].
BARRAND, MA ;
ROBERTSON, KJ ;
VONWEIKERSTHAL, SF .
FEBS LETTERS, 1995, 374 (02) :179-183
[3]   Role of multidrug resistance P-glycoprotein in the secretion of aldosterone by human adrenal NCI-H295 cells [J].
Bello-Reuss, E ;
Ernest, S ;
Holland, OB ;
Hellmich, MR .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2000, 278 (06) :C1256-C1265
[4]   What have we learnt thus far from mice with disrupted P-glycoprotein genes? [J].
Borst, P ;
Schinkel, AH .
EUROPEAN JOURNAL OF CANCER, 1996, 32A (06) :985-990
[5]   In situ transport of vinblastine and selected P-glycoprotein substrates:: Implications for drug-drug interactions at the mouse blood-brain barrier [J].
Cisternino, S ;
Rousselle, C ;
Debray, M ;
Scherrmann, JM .
PHARMACEUTICAL RESEARCH, 2004, 21 (08) :1382-1389
[6]   MULTIDRUG-RESISTANCE GENE (P-GLYCOPROTEIN) IS EXPRESSED BY ENDOTHELIAL-CELLS AT BLOOD-BRAIN BARRIER SITES [J].
CORDONCARDO, C ;
OBRIEN, JP ;
CASALS, D ;
RITTMANGRAUER, L ;
BIEDLER, JL ;
MELAMED, MR ;
BERTINO, JR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (02) :695-698
[7]   Development of an in situ mouse brain perfusion model and its application to mdr1a P-glycoprotein-deficient mice [J].
Dagenais, C ;
Rousselle, C ;
Pollack, GM ;
Scherrmann, JM .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2000, 20 (02) :381-386
[8]   RELATIVE BINDING-AFFINITY OF STEROIDS FOR THE CORTICOSTERONE RECEPTOR SYSTEM IN RAT HIPPOCAMPUS [J].
DEKLOET, ER ;
VELDHUIS, HD ;
WAGENAARS, JL ;
BERGINK, EW .
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 1984, 21 (02) :173-178
[9]   Three-dimensional cerebral vasculature of the CBA mouse brain: A magnetic resonance imaging and micro computed tomography study [J].
Dorr, A. ;
Sled, J. G. ;
Kabani, N. .
NEUROIMAGE, 2007, 35 (04) :1409-1423
[10]   The distribution of the anti-HIV drug, 2′3′-dideoxycytidine (ddC), across the blood-brain and blood-cerebrospinal fluid barriers and the influence of organic anion transport inhibitors [J].
Gibbs, JE ;
Thomas, SA .
JOURNAL OF NEUROCHEMISTRY, 2002, 80 (03) :392-404