Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs

Schinkel, Alfred H.; Smit, Jan Maerten; Tellingen, Olaf van; Beijnen, Jos H.; Wagenaar, Els; Deemter, Liesbeth van; Mol, C. A. A. M.; Valk, Martin A. van der; Robanus-Maandag, Els C.; Riele, Hein P. J. te; Berns, Anton; Borst, Piet

doi:10.1016/0092-8674(94)90212-7

Cited by 2,072 publications

(1,481 citation statements)

References 39 publications

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“…8 biochemical evidence for the presence of P-gp in BeWo cells and the primary cultures was confirmed by immunoblotting experiments. The C219 monoclonal antibody used in these experiments is specific for MDR1 [29,30] and the positive findings were in good agreement with the literature [24,31] for normal human trophoblasts.…”

Section: Discussionsupporting

confidence: 89%

Functional expression of P-glycoprotein in primary cultures of human cytotrophoblasts and BeWo cells☆

Utoguchi

Chandorkar

Avery

et al. 2000

Reproductive Toxicology

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Section: Discussionsupporting

confidence: 89%

Functional expression of P-glycoprotein in primary cultures of human cytotrophoblasts and BeWo cells☆

Utoguchi

Chandorkar

Avery

et al. 2000

Reproductive Toxicology

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“…the in¯uence of PGP on drug pharmacokinetics in vivo (Schinkel et al, 1994(Schinkel et al, , 1995. However, the potential usefulness of this model in understanding the precise role that PGP plays in controlling permeability in speci®c tissues such as the intestine has not been addressed.…”

Section: Discussionmentioning

confidence: 99%

“…Although mdr1b is absent from the intestine of normal mice (Croop et al, 1989), the expression of this gene is known to be upregulated in the kidney and liver of mdr1a (7/7) mice (Schinkel et al, 1994). To investigate potential compensatory e ects in intestine the transport of paclitaxel and etoposide was measured in intestine from mice in which both mdr1a and mdr1b expression had been ablated (Figure 7).…”

Section: Lack Of Involvement Of Mdr1b In Drug Efflux In Mouse Intestinementioning

confidence: 99%

“…Transgenic animal models, in which speci®c transporter genes have been disrupted (Schinkel et al, 1994;Lorico et al, 1997), represent important tools with which to address these questions. The mdr1a (7/7) mouse strain developed by Schinkel and co-workers has thus far, been used primarily to demonstrate PGP-mediated e ects on in vivo toxicity and pharmacokinetics (Schinkel et al, 1994(Schinkel et al, , 1995Fromm et al, 1999;Yokogawa et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…The mdr1a (7/7) mouse strain developed by Schinkel and co-workers has thus far, been used primarily to demonstrate PGP-mediated e ects on in vivo toxicity and pharmacokinetics (Schinkel et al, 1994(Schinkel et al, , 1995Fromm et al, 1999;Yokogawa et al, 1999). Given that several factors in addition to intestinal absorption will determine drug bioavailability, such studies cannot provide direct information on the in¯uence of PGP ablation on drug e ux and permeability at the level of intestinal tissue.…”

Section: Introductionmentioning

confidence: 99%

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Resolution of P‐glycoprotein and non‐P‐glycoprotein effects on drug permeability using intestinal tissues from mdr1a (−/−) mice

Stephens

O’Neill

Bennett

et al. 2002

British J Pharmacology

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1 Intestinal xenobiotic transporters are a signi®cant barrier to the absorption of many orally administered drugs. P-glycoprotein (PGP) is the best known, but several others, including members of the multidrug resistance-associated protein (MRP) family, are also expressed. De®nitive information on their precise e ect on intestinal drug permeability is scarce due to a lack of speci®c inhibitors and the di culty of studying non-PGP activity in the presence of high PGP expression. 2 We have investigated the in vitro use of intestinal tissues from PGP knockout (mdr1a (7/7)) mice as a tool for dissecting the mechanisms of intestinal drug e ux. The permeability characteristics of digoxin (DIG), paclitaxel (TAX) and etoposide (ETOP) were measured in ileum from mdr1a (7/7) and wild-type (FVB) mice mounted in Ussing chambers. 3 DIG and TAX exhibited marked e ux across FVB tissues (B-A : A-B apparent permeability (P app ) ratio 10 and 17 respectively) which was absent in mdr1a (7/7) tissues, con®rming that PGP is the sole route of intestinal e ux for these compounds. The A-B P app of both compounds was 3 ± 5 fold higher in mdr1a (7/7) than in FVB. 4 Polarized transport of ETOP in FVB tissues was reduced but not abolished in mdr1a (7/7) tissues. Residual ETOP e ux in mdr1a (7/7) tissues was abolished by the MRP inhibitor MK571, indicating involvement of both PGP and MRP. 5 MK571 abolished calcein e ux in mdr1a (7/7) tissues, while quinidine had no parallel e ect in FVB tissues, suggesting involvement of MRP but not PGP. 6 Tissues from mdr1a (7/7) mice provide a novel approach for investigating the in¯uence of PGP ablation on intestinal permeability and for resolving PGP and non-PGP mechanisms that modulate drug permeability.

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Effect of MDR1 Haplotype on Risk of Parkinson Disease

Tan¹,

Chan²,

Ng³

et al. 2005

Arch Neurol

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Background: MDR1, a multidrug transporter, encodes a P-glycoprotein that regulates the bioavailability of xenobiotics and is highly expressed at the blood-brainbarrier. Two single nucleotide polymorphisms (SNPs) (e21/ 2677[G/T/A] and e26/3435[C/T]) in the MDR1 gene can lead to differences in MDR1 expression and function. Specific MDR1 alleles of the 2 SNPs are positively selected among ethnic Chinese but not in the white population.

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Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs

Cited by 2,072 publications

References 39 publications

Functional expression of P-glycoprotein in primary cultures of human cytotrophoblasts and BeWo cells☆

Functional expression of P-glycoprotein in primary cultures of human cytotrophoblasts and BeWo cells☆

Resolution of P‐glycoprotein and non‐P‐glycoprotein effects on drug permeability using intestinal tissues from mdr1a (−/−) mice

Effect of MDR1 Haplotype on Risk of Parkinson Disease

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