ABC drug transporters: hereditary polymorphisms and pharmacological impact in MDR1, MRP1 and MRP2

Kerb, Reinhold; Hoffmeyer, Sven; Brinkmann, Ulrich

doi:10.1517/14622416.2.1.51

Cited by 175 publications

(69 citation statements)

References 103 publications

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“…However, these studies indicate that common polymorphisms that affect P-gp do not have global effects on its pump function. Taken together with the recent work of Hoffmeyer et al (2000) and Kerb et al (2001), polymorphisms that are linked to alterations in P-gp expression are more likely to be clinically significant than those studied here, which change coding sequence.…”

Section: Characterization Of Polymorphisms In the Human Mdr1 Genesupporting

confidence: 56%

“…Several recent reports indicate that polymorphisms are relatively common in the human MDR1 gene (Yoshimoto et al, 1988;Mickley et al, 1998;Decleves et al, 2000;Hoffmeyer et al, 2000;Liu and Hu 2000;Ameyaw et al, 2001;Brinkmann et al, 2001;Cascorbi et al, 2001;Hitzl et al, 2001;Ito et al, 2001;Kerb et al, 2001;Kim et al, 2001;Schaeffeler et al, 2001). This finding has stimulated interest in whether common coding polymorphisms affect function of P-gp and/or whether polymorphic variants are linked to altered drug pharmacokinetics.…”

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confidence: 99%

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Functional Characterization of Coding Polymorphisms in the HumanMDR1 Gene Using a Vaccinia Virus Expression System

2002

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The human MDR1-encoded transporter is a 170-kDa plasma membrane glycoprotein [P-glycoprotein (P-gp)] capable of binding and energy-dependent extrusion of structurally diverse organic compounds and drugs. P-gp seems to play a significant role in uptake, distribution, and excretion of many different drugs. To determine whether common polymorphic forms of P-gp are likely to alter function of P-gp, we characterized five known MDR1 coding polymorphisms (N21D, F103L, S400N, A893S, and A998T) using a vaccinia virus-based transient expression system. Cell surface expression of wild-type P-gp was time-dependent over a time course of 5.5 to 34.5 h; highest expression was obtained by 22 to 26.5 h after infection/transfection, indicating that a semiquantitative assay for P-gp expression levels was possible. HeLa cells stained with the P-gp specific monoclonal antibodies MRK-16 and Western blots probed with C219 revealed similar cell surface expression for the polymorphisms and for wild-type protein. Time-dependent P-gp pump function maximal at 22 h after infection/transfection was demonstrated for the following MDR1 fluorescence substrates: 4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoic acid, succinimidyl ester (bodipy-FL)-verapamil, bodipy-FL-vinblastine, calcein-AM, bodipy-FL-prazosin, bisantrene, and bodipy-FL-forskolin, but not for daunorubicin. Transport studies of all tested substrates indicated that the substrate specificity of the pump was not substantially affected by any of the tested polymorphisms. Cell surface expression and function of double mutants including the more common polymorphisms (N21D-S400N, N21D-A893S, and S400N-A893S) showed no differences from wild-type. These results demonstrate that the common MDR1 coding polymorphisms result in P-gps with a cell surface distribution and function similar to wild-type P-gp.

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Section: Characterization Of Polymorphisms In the Human Mdr1 Genesupporting

confidence: 56%

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confidence: 99%

Functional Characterization of Coding Polymorphisms in the HumanMDR1 Gene Using a Vaccinia Virus Expression System

2002

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“…66 In addition to intrinsic or acquired overexpression of multidrug transporters in the BBB of patients with epilepsy, functional polymorphisms of these transporters may play a role in pharmacoresistance. 75,76 Furthermore, both overexpression and functional polymorphisms of multidrug transporters in patients with intractable epilepsy need not necessarily be restricted to the brain, but could also occur in other tissues, such as the small intestine, where PGP is thought to form a barrier against entrance of drugs from the interstinal lumen into the bloodstream, thereby limiting their oral bioavailability. 4 In this respect, it is interesting to note that Lazarowski et al 77 have reported persistent subtherapeutic plasma levels of AEDs (including phenytoin and phenobarbital) despite aggressive and continuous AED administration in a patient with refractory epilepsy associated with overexpression of MDR1.…”

Section: Role Of the Bbb Abc Transporters In Drug Resistancementioning

confidence: 99%

Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

2005

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Summary:The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from potentially harmful endogenous and exogenous substances. BBB active drug efflux transporters of the ATP-binding cassette (ABC) gene family are increasingly recognized as important determinants of drug distribution to, and elimination from, the CNS. The ABC efflux transporter P-glycoprotein (Pgp) has been demonstrated as a key element of the BBB that can actively transport a huge variety of lipophilic drugs out of the brain capillary endothelial cells that form the BBB. In addition to Pgp, other ABC efflux transporters such as members of the multidrug resistance protein (MRP) family and breast cancer resistance protein (BCRP) seem to contribute to BBB function. Consequences of ABC efflux transporters in the BBB include minimizing or avoiding neurotoxic adverse effects of drugs that otherwise would penetrate into the brain. However, ABC efflux transporters may also limit the central distribution of drugs that are beneficial to treat CNS diseases. Furthermore, neurological disorders such as epilepsy may be associated with overexpression of ABC efflux transporters at the BBB, resulting in pharmacoresistance to therapeutic medication. Therefore, modulation of ABC efflux transporters at the BBB forms a novel strategy to enhance the penetration of drugs into the brain and may yield new therapeutic options for drug-resistant CNS diseases.

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“…Phase II metabolizing or conjugating enzymes consist of many superfamilies of enzymes mainly including sulfotransferases (SULT) [3], UDPglucuronosyltransferases (UGT) [4], and glutathione transferases [5]. Efflux transporters, including p-glycoprotein (p-gp) [6], multidrug resistance associated proteins (MRPs) [6], and organic anion transporter (OAT) [7] are expressed in many tissues such as the liver, intestine, kidney and brain, where they present a formidable barrier to drug penetration, and play crucial roles in drug absorption, distribution and excretion [6,8,9]. Drugs that undergo extensive phase I metabolism, phase II conjugation and/or efflux by various transporters have poor bioavailability and are more prone to metabolism-based drug interactions.…”

Section: Introductionmentioning

confidence: 99%

Natural polyphenol disposition via coupled metabolic pathways

Liu¹,

Hu²

2007

Expert Opinion on Drug Metabolism & Toxicology

126

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A major challenge associated with the development of chemopreventive polyphenols is the lack of bioavailability in vivo, which are primarily the result of coupled metabolic activities of conjugating enzymes and efflux transporters. These coupling processes are present in most of tissues and organs in mammals and are efficient for the purposes of drug metabolism, elimination and detoxification. Therefore, it was expected that these coupling processes represent a significant barrier to the oral bioavailabilities of polyphenols. In various studies of this coupling process, it was identified that various conjugating enzymes such as UGT and SULT are capable of producing very hydrophilic metabolites of polyphenols, which cannot diffuse out of the cells and needs the action of efflux transporters to pump them out of the cells. Additional studies have shown that efflux transporters such as MRP2, BCRP and OAT appear to serve as the gate keeper when there is an excess capacity to metabolize the compounds. These efflux transporters may also act as the facilitator of metabolism when there is a product/metabolite inhibition. For polyphenols, these coupled processes enable a duo recycling scheme of enteric and enterohepatic recycling, which allows the polyphenols to be reabsorbed and results in longer than expected apparent plasma half-lives for these compounds and their conjugates. Since the vast majority of polyphenols in plasma are hydrophilic conjugates, more research is needed to determine if the metabolites are active or reactive, which will help explain their mechanism of actions.

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ABC drug transporters: hereditary polymorphisms and pharmacological impact in MDR1, MRP1 and MRP2

Cited by 175 publications

References 103 publications

Functional Characterization of Coding Polymorphisms in the HumanMDR1 Gene Using a Vaccinia Virus Expression System

Functional Characterization of Coding Polymorphisms in the HumanMDR1 Gene Using a Vaccinia Virus Expression System

Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

Natural polyphenol disposition via coupled metabolic pathways

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