Changes in the brain accumulation of glucocorticoids in abcb1a-deficient CF-1 mice.
The multidrug resistance transporter, P-glycoprotein (P-gp), contributes to highly lipophilic molecules penetrating the brain from the blood at a much lower rate than expected, and has numerous substrates, inhibitors and modulators. The drug-transporting isoform of P-gp is coded by a single human gene, ABCB1, and shares 80% homology with the murine drug-transporting isoforms, abcb1a and abcb1b, which share 92% homology with each other. Although these murine isoforms are highly similar, there are known affinity differences between the isoforms, and the localisation of the two isoforms in the brain is also disputed. Studies using mice genetically modified to be deficient in one or both isoforms of P-gp have also resulted in conflicting data. The contribution of the abcb1a isoform, which is considered to contribute most to the central nervous system (CNS)-protective role of P-gp, is investigated in the present study using CF-1-abcb1a(-/-) mice and the well-established brain/choroid plexus perfusion technique. Twenty-minute in situ brain/choroid plexus perfusions in CF-1-abcb1a(-/-) mice indicated the increased accumulation of [(3) H]cortisol, [(3) H]corticosterone and [(3) H]dexamethasone in most of the brain regions examined compared to CF-1-abcb1a(+/+) mice. Taken together with our earlier published studies in abcb1a/b(-/-) mice, these data strongly suggest that the in vivo CNS accumulation of glucocorticoids obtained using single knockout strains [e.g. abcb1a(-/-)] cannot be directly compared with those obtained in double knockout strains [e.g. abcb1a/b(-/-)].
Institute of Pharmaceutical Science, King's College London, London, UK. brittany.mason@utsouthwestern.edu
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Mason
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Pariante
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Thomas
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000235:genetics; D002196:Capillaries / Q000737:chemistry / Q000378:metabolism; D002831:Choroid Plexus / Q000737:chemistry / Q000378:metabolism; D003345:Corticosterone / Q000032:analysis / Q000378:metabolism; D003907:Dexamethasone / Q000032:analysis / Q000378:metabolism; D005938:Glucocorticoids / Q000032:analysis / Q000378:metabolism*; D006854:Hydrocortisone / Q000032:analysis / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010902:Pituitary Gland / Q000737:chemistry / Q000378:metabolism
D018435:ATP Binding Cassette Transporter, Subfamily B; D005938:Glucocorticoids; D003907:Dexamethasone; C095122:multidrug resistance protein 3; D003345:Corticosterone; D006854:Hydrocortisone