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P-glycoprotein: from genomics to mechanism

Oncogene volume 22, pages 7468–7485 (2003)Cite this article

Abstract

Resistance to chemically different natural product anti-cancer drugs (multidrug resistance, or MDR) results from decreased drug accumulation, resulting from expression of one or more ATP-dependent efflux pumps. The first of these to be identified was P-glycoprotein (P-gp), the product of the human MDR1 gene, localized to chromosome 7q21. P-gp is a member of the large ATP-binding cassette (ABC) family of proteins. Although its crystallographic 3-D structure is yet to be determined, sequence analysis and comparison to other ABC family members suggest a structure consisting of two transmembrane (TM) domains, each with six TM segments, and two nucleotide-binding domains. In the epithelial cells of the gastrointestinal tract, liver, and kidney, and capillaries of the brain, testes, and ovaries, P-gp acts as a barrier to the uptake of xenobiotics, and promotes their excretion in the bile and urine. Polymorphisms in the MDR1 gene may affect the pharmacokinetics of many commonly used drugs, including anticancer drugs. Substrate recognition of many different drugs occurs within the TM domains in multiple-overlapping binding sites. We have proposed a model for how ATP energizes transfer of substrates from these binding sites on P-gp to the outside of the cell, which accounts for the apparent stoichiometry of two ATPs hydrolysed per molecule of drug transported. Understanding of the biology, genetics, and biochemistry of P-gp promises to improve the treatment of cancer and explain the pharmacokinetics of many commonly used drugs.

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Abbreviations

ABC:

ATP-binding cassette

IAAP:

iodoarylazidoprazosin

MDR:

multidrug resistance

P-gp:

P-glycoprotein

TM:

transmembrane

Vi:

orthovanadate

References

  • Allikmets R, Schriml LM, Hutchinson A, Romano-Spica V and Dean M . (1998). Cancer Res., 58, 5337–5339.

  • Al-Shawi MK, Urbatsch IL and Senior AE . (1994). J. Biol. Chem., 269, 8986–8992.

  • Ambudkar SV, Cardarelli CO, Pashinsky I and Stein WD . (1997). J. Biol. Chem., 272, 21160–21166.

  • Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I and Gottesman MM . (1999). Annu. Rev. Pharmacol. Toxicol., 39, 361–398.

  • Ambudkar SV, Lelong IH, Zhang J, Cardarelli CO, Gottesman MM and Pastan I . (1992). Proc. Natl. Acad. Sci. USA, 89, 8472–8476.

  • Ameyaw MM, Regateiro F, Li T, Liu X, Tariq M, Mobarek A, Thornton N, Folayan GO, Githang'a J, Indalo A, Ofori-Adjei D, Price-Evans DA and McLeod HL . (2001). Pharmacogenetics, 11, 217–221.

  • Andrus MB, Turner TM, Sauna ZE and Ambudkar SV . (2000). Bioorg. Med. Chem. Lett., 10, 2275–2278.

  • Belinsky MG and Kruh GD . (1999). Br. J. Cancer, 80, 1342–1349.

  • Bergen AAB, Plomp AS, Schuurman EJ, Terry S, Breuning M, Dauwerse H, Swart J, Kool M, van Soest S, Baas F, ten Brink JB and de Jong P . (2000). Nat. Genet., 25, 228–231.

  • Bohm A, Diez J, Diederichs K, Welte W and Boos W . (2002). J. Biol. Chem., 277, 3708–3718.

  • Borchers C, Boer R, Klemm K, Figala V, Denzinger T, Ulrich WR, Haas S, Ise W, Gekeler V and Przybylski M . (2002). Mol. Pharmacol., 61, 1366–1376.

  • Borst P and Elferink RO . (2002). Annu. Rev. Biochem., 71, 537–592.

  • Borst P, Evers R, Kool M and Wijnholds J . (1999). Biochim. Biophys. Acta, 1461, 347–357.

  • Borst P, Evers R, Kool M and Wijnholds J . (2000). J. Natl. Cancer Inst., 92, 1295–1302.

  • Brangi M, Litman T, Ciotti M, Nishiyama K, Kohlhagen G, Takimoto C, Robey R, Pommier Y, Fojo T and Bates SE . (1999). Cancer Res., 59, 5938–5946.

  • Brinkmann U, Roots I and Eichelbaum M . (2001). Drug Discov. Today, 6, 835–839.

  • Bruggemann EP, Currier SJ, Gottesman MM and Pastan I . (1992). J. Biol. Chem., 267, 21020–21026.

  • Bruggemann EP, Germann UA, Gottesman MM and Pastan I . (1989). J. Biol. Chem., 264, 15483–15488.

  • Brumme ZL, Dong WW, Chan KJ, Hogg RS, Montaner JS, O’Shaughnessy MV and Harrigan PR . (2003). AIDS, 17, 201–208.

  • Bunting KD . (2002). Stem Cells, 20, 11–20.

  • Calado RT, Falcao RP, Garcia AB, Gabellini SM, Zago MA and Franco RF . (2002). Haematologica, 87, 564–568.

  • Cascorbi I, Gerloff T, Johne A, Meisel C, Hoffmeyer S, Schwab M, Schaeffeler E, Eichelbaum M, Brinkmann U and Roots I . (2001). Clin. Pharmacol. Ther., 69, 169–174.

  • Chang G and Roth CB . (2001). Science, 293, 1793–1800.

  • Chen CJ, Chin JE, Ueda K, Clark DP, Pastan I, Gottesman MM and Roninson IB . (1986). Cell, 47, 381–389.

  • Chen CJ, Clark D, Ueda K, Pastan I, Gottesman MM and Roninson IB . (1990). J. Biol. Chem., 265, 506–514.

  • Chen ZS, Lee K and Kruh GD . (2001). J. Biol. Chem., 276, 33747–33754.

  • Chen ZS, Hopper-Borge E, Belinsky MG, Shchaveleva I, Kotova E and Kruh GD . (2003). Mol. Pharmacol., 63, 351–358.

  • Childs S, Yeh RL, Hui D and Ling V . (1998). Cancer Res., 58, 4160–4167.

  • Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, Stewart AJ, Kurz EU, Duncan AM and Deeley RG . (1992). Science, 258, 1650–1654.

  • Dale MP and Hackney DD . (1987). Biochemistry, 26, 8365–8372.

  • de Vree JM, Jacquemin E, Sturm E, Cresteil D, Bosma PJ, Aten J, Deleuze JF, Desrochers M, Burdelski M, Bernard O, Oude Elferink RP and Hadchouel M . (1998). Proc. Natl. Acad. Sci. USA, 95, 282–287.

  • Dean M, Hamon Y and Chimini G . (2001). J. Lipid Res., 42, 1007–1017.

  • Decleves X, Chevillard S, Charpentier C, Vielh P and Laplanche JL . (2000). Hum. Mutat., 15, 486.

  • Demeule M, Laplante A, Murphy GF, Wenger RM and Beliveau R . (1998). Biochemistry, 37, 18110–18118.

  • Demmer A, Andreae S, Thole H and Tummler B . (1999). Eur. J. Biochem., 264, 800–805.

  • Demmer A, Thole H, Kubesch P, Brandt T, Raida M, Fislage R and Tummler B . (1997). J. Biol. Chem., 272, 20913–20919.

  • Diederichs K, Diez J, Greller G, Muller C, Breed J, Schnell C, Vonrhein C, Boos W and Welte W . (2000). EMBO J., 19, 5951–5961.

  • Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK and Ross DD . (1998). Proc. Natl. Acad. Sci. USA, 95, 15665–15670.

  • Drescher S, Schaeffeler E, Hitzl M, Hofmann U, Schwab M, Brinkmann U, Eichelbaum M and Fromm MF . (2002). Br. J. Clin. Pharmacol., 53, 526–534.

  • Ecker G, Huber M, Schmid D and Chiba P . (1999). Mol. Pharmacol., 56, 791–796.

  • Ecker GF, Csaszar E, Kopp S, Plagens B, Holzer W, Ernst W and Chiba P . (2002). Mol. Pharmacol., 61, 637–648.

  • Ejendal KFK and Hrycyna CA . (2002). Curr. Protein Pept. Sci., 3, 503–511.

  • Evans WE and McLeod HL . (2003). N. Engl. J. Med., 348, 538–549.

  • Fisher AJ, Smith CA, Thoden JB, Smith R, Sutoh K, Holden HM and Rayment I . (1995). Biochemistry, 34, 8960–8972.

  • Fojo AT, Shen DW, Mickley LA, Pastan I and Gottesman MM . (1987). J. Clin. Oncol., 5, 1922–1927.

  • Ford JM and Hait WN . (1990). Pharmacol. Rev., 42, 155–199.

  • Furuno T, Landi MT, Ceroni M, Caporaso N, Bernucci I, Nappi G, Martignoni E, Schaeffeler E, Eichelbaum M, Schwab M and Zanger UM . (2002). Pharmacogenetics, 12, 529–534.

  • Gaudet R and Wiley DC . (2001). EMBO J., 20, 4964–4972.

  • Gerloff T, Stieger B, Hagenbuch B, Madon J, Landmann L, Roth J, Hofmann AF and Meier PJ . (1998). J. Biol. Chem., 273, 10046–10050.

  • Germann UA, Chambers TC, Ambudkar SV, Licht T, Cardarelli CO, Pastan I and Gottesman MM . (1996). J. Biol. Chem., 271, 1708–1716.

  • Goh BC, Lee SC, Wang LZ, Fan L, Guo JY, Lamba J, Schuetz E, Lim R, Lim HL, Ong AB and Lee HS . (2002). J. Clin. Oncol., 20, 3683–3690.

  • Goldstein L, Galski H, Fojo A, Willingham M, Lai S, Gazdar A, Pirker R, Green A, Crist W and Brodeur G . (1989). JNCI Cancer Spectrum, 81, 116–124.

  • Goto M, Masuda S, Saito H, Uemoto S, Kiuchi T, Tanaka K and Inui K . (2002). Pharmacogenetics, 12, 451–457.

  • Gottesman MM and Ambudkar SV . (2001). J. Bioenerg. Biomembr., 33, 453–458.

  • Gottesman MM, Fojo T and Bates SE . (2002). Nat. Rev. Cancer, 2, 48–58.

  • Gottesman MM, Hrycyna CA, Schoenlein PV, Germann UA and Pastan I . (1995). Annu. Rev. Genet., 29, 607–649.

  • Gottesman MM and Pastan I . (1988). J. Biol. Chem., 263, 12163–12166.

  • Gottesman MM and Pastan I . (1993). Annu. Rev. Biochem., 62, 385–427.

  • Gottesman MM, Pastan I and Ambudkar SV . (1996). Curr. Opin. Genet. Dev., 6, 610–617.

  • Gottesman MM . (1988). J. Natl. Cancer Inst., 80, 1352–1353.

  • Gottesman MM . (2002). Annu. Rev. Med., 53, 615–627.

  • Greenberger LM . (1993). J. Biol. Chem., 268, 11417–11425.

  • Gribar JJ, Ramachandra M, Hrycyna CA, Dey S and Ambudkar SV . (2000). J. Membr. Biol., 173, 203–214.

  • Hitzl M, Drescher S, van der Kuip H, Schaffeler E, Fischer J, Schwab M, Eichelbaum M and Fromm MF . (2001). Pharmacogenetics, 11, 293–298.

  • Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M and Brinkmann U . (2000). Proc. Natl. Acad. Sci. USA, 97, 3473–3478.

  • Honjo Y, Hrycyna CA, Yan QW, Medina-Perez WY, Robey RW, van de Laar A, Litman T, Dean M and Bates SE . (2001). Cancer Res., 61, 6635–6639.

  • Horinouchi M, Sakaeda T, Nakamura T, Morita Y, Tamura T, Aoyama N, Kasuga M and Okumura K . (2002). Pharm. Res., 19, 1581–1585.

  • Hrycyna CA . (2001). Semin. Cell Dev. Biol., 12, 247–256.

  • Hrycyna CA, Ramachandra M, Ambudkar SV, Ko YH, Pedersen PL, Pastan I and Gottesman MM . (1998). J. Biol. Chem., 273, 16631–16634.

  • Hrycyna CA, Ramachandra M, Germann UA, Cheng PW, Pastan I and Gottesman MM . (1999). Biochemistry, 38, 13887–13899.

  • Hung LW, Wang IX, Nikaido K, Liu PQ, Ames GF and Kim SH . (1998). Nature, 396, 703–707.

  • Illmer T, Schuler US, Thiede C, Schwarz UI, Kim RB, Gotthard S, Freund D, Schakel U, Ehninger G and Schaich M . (2002). Cancer Res., 62, 4955–4962.

  • Isenberg B, Thole H, Tummler B and Demmer A . (2001). Eur. J. Biochem., 268, 2629–2634.

  • Ito K, Suzuki H, Hirohashi T, Kume K, Shimizu T and Sugiyama Y . (1997). Am. J. Physiol., 35, G16–G22.

  • Ito S, Ieiri I, Tanabe M, Suzuki A, Higuchi S and Otsubo K . (2001). Pharmacogenetics, 11, 175–184.

  • Jedlitschky G, Burchell B and Keppler D . (2000). J. Biol. Chem., 275, 30069–30074.

  • Jedlitschky G, Leier I, Buchholz U, Barnouin K, Kurz G and Keppler D . (1996). Cancer Res., 56, 988–994.

  • Johne A, Kopke K, Gerloff T, Mai I, Rietbrock S, Meisel C, Hoffmeyer S, Kerb R, Fromm MF, Brinkmann U, Eichelbaum M, Brockmoller J, Cascorbi I and Roots I . (2002). Clin. Pharmacol. Ther., 72, 584–594.

  • Johnson DR, Finch RA, Lin ZP, Zeiss CJ and Sartorelli AC . (2001). Cancer Res., 61, 1469–1476.

  • Karpowich N, Martsinkevich O, Millen L, Yuan YR, Dai PL, MacVey K, Thomas PJ and Hunt JF . (2001). Structure (Camb), 9, 571–586.

  • Kartenbeck J, Leuschner U, Mayer R and Keppler D . (1996). Hepatology, 23, 1061–1066.

  • Kerb R, Aynacioglu AS, Brockmoller J, Schlagenhaufer R, Bauer S, Szekeres T, Hamwi A, Fritzer-Szekeres M, Baumgartner C, Ongen HZ, Guzelbey P, Roots I and Brinkmann U . (2001a). Pharmacogenomics J., 1, 204–210.

  • Kerb R, Hoffmeyer S and Brinkmann U . (2001b). Pharmacogenomics, 2, 51–64.

  • Kerr KM, Sauna ZE and Ambudkar SV . (2001). J. Biol. Chem., 276, 8657–8664.

  • Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, Taylor A, Xie HG, McKinsey J, Zhou S, Lan LB, Schuetz JD, Schuetz EG and Wilkinson GR . (2001). Clin. Pharmacol. Ther., 70, 189–199.

  • Kimchi-Sarfaty C, Gribar JJ and Gottesman MM . (2002). Mol. Pharmacol., 62, 1–6.

  • Kioka N, Tsubota J, Kakehi Y, Komano T, Gottesman MM, Pastan I and Ueda K . (1989). Biochem. Biophys. Res. Commun., 162, 224–231.

  • Komatani H, Kotani H, Hara Y, Nakagawa R, Matsumoto M, Arakawa H and Nishimura S . (2001). Cancer Res., 61, 2827–2832.

  • Konings WN and Poelarends GJ . (2002). IUBMB Life, 53, 213–218.

  • Kool M, van der Linden M, de Haas M, Scheffer GL, de Vree JML, Smith AJ, Jansen G, Peters GJ, Ponne N, Scheper RJ, Elferink R, Baas F and Borst P . (1999b). Proc. Natl. Acad. Sci. USA, 96, 6914–6919.

  • Kurata Y, Ieiri I, Kimura M, Morita T, Irie S, Urae A, Ohdo S, Ohtani H, Sawada Y, Higuchi S and Otsubo K . (2002). Clin. Pharmacol. Ther., 72, 209–219.

  • Laing NM, Belinsky MG, Kruh GD, Bell DW, Boyd JT, Barone L, Testa JR and Tew KD . (1998). Cancer Res., 58, 1332–1337.

  • Lecureur V, Sun DX, Hargrove P, Schuetz EG, Kim RB, Lan LB and Schuetz JD . (2000). Mol. Pharmacol., 57, 24–35.

  • Le Saux O, Urban Z, Tschuch C, Csiszar K, Bacchelli B, Quaglino D, Pasquali-Ronchetti I, Pope FM, Richards A, Terry S, Bercovitch L, de Paepe A and Boyd CD . (2000). Nat. Genet., 25, 223–227.

  • Leith CP, Kopecky KJ, Chen IM, Eijdems L, Slovak ML, McConnell TS, Head DR, Weick J, Grever MR, Appelbaum FR and Willman CL . (1999). Blood, 94, 1086–1099.

  • Lelong IH, Cardarelli CO, Gottesman MM and Pastan I . (1994). Biochemistry, 33, 8921–8929.

  • Leonard GD, Polgar O and Bates SE . (2002). Curr. Opin. Invest. Drugs, 3, 1652–1659.

  • List AF, Kopecky KJ, Willman CL, Head DR, Persons DL, Slovak ML, Dorr R, Karanes C, Hynes HE, Doroshow JH, Shurafa M and Appelbaum FR . (2001). Blood, 98, 3212–3220.

  • Litman T, Brangi M, Hudson E, Fetsch P, Abati A, Ross DD, Miyake K, Resau JH and Bates SE . (2000). J. Cell Sci., 113, 2011–2021.

  • Litman T, Druley TE, Stein WD and Bates SE . (2001). Cell Mol. Life Sci., 58, 931–959.

  • Liu CE, Liu PQ and Ames GFL . (1997). J. Biol. Chem., 272, 21883–21891.

  • Locher KP, Lee AT and Rees DC . (2002). Science, 296, 1091–1098.

  • Loe DW, Deeley RG and Cole SP . (1996). Eur. J. Cancer, 32A, 945–957.

  • Loe DW, Deeley RG and Cole SP . (1998). Cancer Res., 58, 5130–5136.

  • Loo TW and Clarke DM . (1995a). J. Biol. Chem., 270, 22957–22961.

  • Loo TW and Clarke DM . (1995b). J. Biol. Chem., 270, 21449–21452.

  • Loo TW and Clarke DM . (1999a). Biochem. Cell Biol., 77, 11–23.

  • Loo TW and Clarke DM . (1999b). J. Biol. Chem., 274, 24759–24765.

  • Loo TW and Clarke DM . (2001a). J. Biol. Chem., 276, 31800–31805.

  • Loo TW and Clarke DM . (2001b). J. Biol. Chem., 276, 14972–14979.

  • Loo TW and Clarke DM . (2001c). J. Biol. Chem., 276, 36877–36880.

  • Loo TW and Clarke DM . (2002a). J. Biol. Chem., 277, 44332–44338.

  • Loo TW and Clarke DM . (2002b). Proc. Natl. Acad. Sci. USA, 99, 3511–3516.

  • Maliepaard M, Scheffer GL, Faneyte lF, van Gastelen MA, Pijnenborg AC, Schinkel AH, van De Vijver MJ, Scheper RJ and Schellens JH . (2001). Cancer Res., 61, 3458–3464.

  • Mayer U, Wagenaar E, Beijnen JH, Smit JW, Meijer DK, van Asperen J, Borst P and Schinkel AH . (1996). Br. J. Pharmacol., 119, 1038–1044.

  • Mickley LA, Lee JS, Weng Z, Zhan Z, Alvarez M, Wilson W, Bates SE and Fojo T . (1998). Blood, 91, 1749–1756.

  • Mimmack ML, Gallagher MP, Pearce SR, Hyde SC, Booth IR and Higgins CF . (1989). Proc. Natl. Acad. Sci. USA, 86, 8257–8261.

  • Miyake K, Mickley L, Litman T, Zhan Z, Robey R, Cristensen B, Brangi M, Greenberger L, Dean M, Fojo T and Bates SE . (1999). Cancer Res., 59, 8–13.

  • Moriya Y, Nakamura T, Horinouchi M, Sakaeda T, Tamura T, Aoyama N, Shirakawa T, Gotoh A, Fujimoto S, Matsuo M, Kasuga M and Okumura K . (2002). Biol. Pharm. Bull., 25, 1356–1359.

  • Morris DI, Greenberger LM, Bruggemann EP, Cardarelli C, Gottesman MM, Pastan I and Seamon KB . (1994). Mol. Pharmacol., 46, 329–337.

  • Muller M, Meijer C, Zaman GJR, Borst P, Scheper RJ, Mulder NH, Devries EGE and Jansen PLM . (1994). Proc. Natl. Acad. Sci. USA, 91, 13033–13037.

  • Nooter K, Westerman AM, Flens MJ, Zaman GJR, Scheper RJ, vanWingerden KE, Burger H, Oostrum R, Boersma T, Sonneveld P, Gratama JW, Kok T, Eggermont AMM, Bosman FT and Stoter G . (1995). Clin. Cancer Res., 1, 1301–1310.

  • Paulusma CC, Bosma PJ, Zaman GJR, Bakker CTM, Otter M, Scheffer GL, Scheper RJ, Borst P and Elferink R . (1996). Science, 271, 1126–1128.

  • Paulusma CC, Kool M, Bosma PJ, Scheffer GL, terBorg F, Scheper RJ, Tytgat GNJ, Borst P, Baas F and Elferink PJO . (1997). Hepatology, 25, 1539–1542.

  • Potocnik U, Glavac MR, Golouh R and Glavac D . (2001). Pflugers Arch., 442, R182–R183.

  • Ramachandra M, Ambudkar SV, Chen D, Hrycyna CA, Dey S, Gottesman MM and Pastan I . (1998). Biochemistry, 37, 5010–5019.

  • Rayment I . (1996). J. Biol. Chem., 271, 15850–15853.

  • Repke KR . (1982). Ann. NY Acad. Sci., 402, 272–286.

  • Ringpfeil F, Lebwohl MG, Christiano AM and Uitto J . (2000). Proc. Natl. Acad. Sci. USA, 97, 6001–6006.

  • Roberts RL, Joyce PR, Mulder RT, Begg EJ and Kennedy MA . (2002). Pharmacogenomics J., 2, 191–196.

  • Rosenberg MF, Velarde G, Ford RC, Martin C, Berridge G, Kerr ID, Callaghan R, Schmidlin A, Wooding C, Linton KJ and Higgins CF . (2001). EMBO J., 20, 5615–5625.

  • Ruetz S and Gros P . (1994). Cell, 77, 1071–1081.

  • Saito S, Iida A, Sekine A, Miura Y, Ogawa C, Kawauchi S, Higuchi S and Nakamura Y . (2002). J. Hum. Genet., 47, 38–50.

  • Sakaeda T, Nakamura T, Horinouchi M, Kakumoto M, Ohmoto N, Sakai T, Morita Y, Tamura T, Aoyama N, Hirai M, Kasuga M and Okumura K . (2001). Pharm. Res., 18, 1400–1404.

  • Sankaran B, Bhagat S and Senior AE . (1997). Biochemistry, 36, 6847–6853.

  • Sarkadi B, Price EM, Boucher RC, Germann UA and Scarborough GA . (1992). J. Biol. Chem., 267, 4854–4858.

  • Sauna ZE and Ambudkar SV . (2000). Proc. Natl. Acad. Sci. USA, 97, 2515–2520.

  • Sauna ZE and Ambudkar SV . (2001). J. Biol. Chem., 276, 11653–11661.

  • Sauna ZE, Muller M, Peng XH and Ambudkar SV . (2002). Biochemistry, 41, 13989–14000.

  • Sauna ZE, Smith MM, Muller M and Ambudkar SV . (2001a). J. Biol. Chem., 276, 33301–33304.

  • Sauna ZE, Smith MM, Muller M and Ambudkar SV . (2001b). J. Biol. Chem., 276, 21199–21208.

  • Sauna ZE, Smith MM, Muller M, Kerr KM and Ambudkar SV . (2001c). J. Bioenerg. Biomembr., 33, 481–491.

  • Schinkel AH . (1997). Semin. Cancer Biol., 8, 161–170.

  • Schinkel AH, Arceci RJ, Smit JJM, Wagenaar E, Baas F, Dolle M, Tsuruo T, Mechetner EB, Roninson IB and Borst P . (1993). Int. J. Cancer, 55, 478–484.

  • Schuetz JD, Connelly MC, Sun DX, Paibir SG, Flynn PM, Srinivas RV, Kumar A and Fridland A . (1999). Nat. Med., 5, 1048–1051.

  • Schwab M, Eichelbaum M and Fromm MF . (2003). Annu. Rev. Pharmacol. Toxicol., 43, 285–307.

  • Seelig A . (1998a). Eur. J. Biochem., 251, 252–261.

  • Seelig A . (1998b). Int. J. Clin. Pharmacol. Ther., 36, 50–54.

  • Senior AE . (1998). Acta. Physiol. Scand. Suppl., 643, 213–218.

  • Senior AE, al-Shawi MK and Urbatsch IL . (1995). FEBS Lett., 377, 285–289.

  • Senior AE and Bhagat S . (1998). Biochemistry, 37, 831–836.

  • Senior AE and Gadsby DC . (1997). Semin. Cancer Biol., 8, 143–150.

  • Shapiro AB and Ling V . (1998). Eur. J. Biochem., 254, 189–193.

  • Sharma S and Davidson AL . (2000). J. Bacteriol., 182, 6570–6576.

  • Sharom FJ, Yu X, Chu JW and Doige CA . (1995). Biochem. J., 308, 381–390.

  • Sharom FJ, Yu X and Doige CA . (1993). J. Biol. Chem., 268, 24197–24202.

  • Shen DW, Pastan I and Gottesman MM . (1998). Cancer Res., 58, 268–275.

  • Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, Wood NW and Sisodiya SM . (2003). N. Engl. J. Med., 348, 1442–1448.

  • Siegsmund M, Brinkmann U, Schaffeler E, Weirich G, Schwab M, Eichelbaum M, Fritz P, Burk O, Decker J, Alken P, Rothenpieler U, Kerb R, Hoffmeyer S and Brauch H . (2002). J. Am. Soc. Nephrol., 13, 1847–1854.

  • Sinues B, Fanlo A, Bernal ML, Mayayo E, Bello S, Rubio E and Isla D . (2003). Oncology, 64, 183–185.

  • Sleep JA, Hackney DD and Boyer PD . (1980). J. Biol. Chem., 255, 4094–4099.

  • Smit JJ, Schinkel AH, Oude Elferink RP, Groen AK, Wagenaar E, van Deemter L, Mol CA, Ottenhoff R, van der Lugt NM and van Roon MA et al. (1993). Cell, 75, 451–462.

  • Smith CA and Rayment I . (1996). Biochemistry, 35, 5404–5417.

  • Strautnieks SS, Bull LN, Knisely AS, Kocoshis S, Dahl N, Arnell H, Sokal E, Dahan K, Childs S, Ling V, Tanner MS, Kagalwalla AF, Nemeth A, Pawlowska J, Baker A, Mieli-Vergani G, Freimer NB, Gardiner RM and Thompson RJ . (1998). Nat. Genet., 20, 233–238.

  • Struk B, Cai L, Zach S, Chung WJJ, Lumsden A, Stumm M, Huber M, Schaen L, Kim CA, Goldsmith LA, Viljoen D, Figuera LE, Fuchs W, Munier F, Ramesar R, Hohl D, Richards R, Neldner KH and Lindpaintner K . (2000). J. Mol. Med., 78, 282–286.

  • Szabo K, Welker E, Bakos Muller M, Roninson I, Varadi A and Sarkadi B . (1998). J. Biol. Chem., 273, 10132–10138.

  • Tanabe M, Ieiri I, Nagata N, Inoue K, Ito S, Kanamori Y, Takahashi M, Kurata Y, Kigawa J, Higuchi S, Terakawa N and Otsubo K . (2001). J. Pharmacol. Exp. Ther., 297, 1137–1143.

  • Tang K, Ngoi SM, Gwee PC, Chua JM, Lee EJ, Chong SS and Lee CG . (2002). Pharmacogenetics, 12, 437–450.

  • Urbatsch IL, al-Shawi MK and Senior AE . (1994). Biochemistry, 33, 7069–7076.

  • Urbatsch IL, Beaudet L, Carrier I and Gros P . (1998). Biochemistry, 37, 4592–4602.

  • Urbatsch IL, Gimi K, Wilke-Mounts S and Senior AE . (2000a). Biochemistry, 39, 11921–11927.

  • Urbatsch IL, Julien M, Carrier I, Rousseau ME, Cayrol R and Gros P . (2000b). Biochemistry, 39, 14138–14149.

  • Urbatsch IL, Sankaran B, Bhagat S and Senior AE . (1995a). J. Biol. Chem., 270, 26956–26961.

  • Urbatsch IL, Sankaran B, Weber J and Senior AE . (1995b). J. Biol. Chem., 270, 19383–19390.

  • Volk EL, Farley KM, Wu Y, Li F, Robey RW and Schneider E . (2002). Cancer Res., 62, 5035–5040.

  • von Ahsen N, Richter M, Grupp C, Ringe B, Oellerich M and Armstrong VW . (2001). Clin. Chem., 47, 1048–1052.

  • Vulevic B, Chen ZJ, Boyd JT, Davis W, Walsh ES, Belinsky MG and Tew KD . (2001). Cancer Res., 61, 3339–3347.

  • Wang RX, Salem M, Yousef IM, Tuchweber B, Lam P, Childs SJ, Helgason CD, Ackerley C, Phillips MJ and Ling V . (2001). Proc.Natl. Acad. Sci. USA, 98, 2011–2016.

  • Wijholds J, Mol C, van Deemter L, de Haas M, Scheffer GL, Baas F, Beijnen JH, Scheper RJ, Hatse S, De Clercq E, Balzarini J and Borst P . (2000). Proc. Natl. Acad. Sci. USA, 97, 7476–7481.

  • Wu Q, Bounaud PY, Kuduk SD, Yang CP, Ojima I, Horwitz SB and Orr GA . (1998). Biochemistry, 37, 11272–11279.

  • Yamada S and Ikemoto N . (1980). J. Biol. Chem., 255, 3108–3119.

  • Yamauchi A, Ieiri I, Kataoka Y, Tanabe M, Nishizaki T, Oishi R, Higuchi S, Otsubo K and Sugimachi K . (2002). Transplantation, 74, 571–572.

  • Zhou S, Morris JJ, Barnes YX, Lan L, Schuetz JD and Sorrentino BP . (2002). Proc. Natl. Acad. Sci. USA, 99, 12339–12344.

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Acknowledgements

We thank John Gribar for constructing Figure 1 and George Leiman and Joyce Sharrar for help with preparation of the manuscript.

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  1. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, 20892, MD, USA

    Suresh V Ambudkar, Chava Kimchi-Sarfaty, Zuben E Sauna & Michael M Gottesman

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  1. Suresh V Ambudkar
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  2. Chava Kimchi-Sarfaty
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Correspondence to Suresh V Ambudkar.

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Ambudkar, S., Kimchi-Sarfaty, C., Sauna, Z. et al. P-glycoprotein: from genomics to mechanism. Oncogene 22, 7468–7485 (2003). https://doi.org/10.1038/sj.onc.1206948

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