ABCA8,B1,B5 transport xenobiotics from cytosol to extracellular region

Stable Identifier
R-HSA-1467457
Type
Reaction [transition]
Species
Homo sapiens
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Some members of the ABC transporter superfamily are able to mediate the efflux of a broad range of cytotoxic drugs from cells, leading to the name multidrug resistance (MDR) proteins (Seeger and van Veen 2009). The ABCB1 (P-glycoprotein 1[PGP], multidrug resistance protein 1 [MRP1]) is the most characterised MDR (Shen et al. 1986, Gottesman & Pastan 1988). ABCB5 (Frank et al. 2005) and ABCA8 (Tsuruoka et al. 2002) are newer members of MDRs.

The ABCB1 (also known as MDR1, P-glycoprotein, or PGP) is the best characterized xenobiotic transporter of the ABC transporter family (Shen et al. 1986, Gottesman and Pastan 1988). The ABCB1 gene maps to the chromosomal band 7q21, which is frequently gained or amplified in cancer (Genovese et al. 2017). Transcription of ABCB1 is negatively regulated by TP53 (p53) and positively regulated by CEBPB (C/EBPbeta), JUN (AP-1), NFYB (NF-Y) and YBX1 (YB-1) (Chen and Sikic 2012). ABCB1 is a 12-pass transmembrane protein with two ATP-binding domains (Chen et al. 1986, Gottesman et al. 2002).The question of how many molecules of ATP are hydrolyzed for the full conformational change cycle and export of xenobiotic substrates out of the cell is not settled. The best biochemical evidence is for one molecule of ATP (Shapiro and Ling, 1998; with a review of methods). Structural studies point to the binding of two molecules but do not allow statements about ATP hydrolysis stoichiometry (reviewed in Jones and George, 2020).

Many anti-cancer drugs and anti-inflammatory drugs, as well as some antibiotics, are exported from the cell by ABCB1 (reviewed by Ambudkar et al. 1999, Gottesman et al. 2002).

Anti-cancer drugs that are substrates of ABCB1 include:
actinomycin D (Horio et al. 1989, Ambudkar et al. 1992, Hill et al. 2013);
bisantrene (Zhang et al. 1994, Aksentijevich et al. 1996);
daunorubicin (Horio et al. 1989, Ambudkar et al. 1992);
docetaxel (Shirakawa et al. 1999);
doxorubicin (Ueda et al. 1987, Ambudkar et al. 1992);
etoposide (Pastan et al. 1988, Lincke et al. 1990, Klamt et al. 2008);
imatinib (Dai et al. 2003);
irinotecan (Paule et al. 2010, Tagen et al. 2010);
melphalan (Kühne et al. 2009);
paclitaxel (Jang et al. 2001);
temozolomide (Munoz et al. 2015);
teniposide (Boiocchi et al. 1992);
vinblastine (Ueda et al. 1987, Ambudkar et al. 1992);
vincristine (Horio et al. 1989).

Anti-inflammatory drugs that are substrates of ABCB1 include:
budenoside (Dilger et al. 2004);
colchicine (Ueda et al. 1987);
dexamethasone (Gruol et al. 1999, Yates et al. 2003);
methylprednisolone (Yates et al. 2003, Cuppen et al. 2017);
prednisolone (PREDL) (Karssen et al. 2002, Yates et al. 2003);
prednisone (PREDN) (Dilger et al. 2004).
The presence of 11-, 17-, and 21-hydroxyl groups appears to be a critical determinant for transport efficiency of steroids by the efflux pump ABCB1 (MDR1). Prednisone contains the 17-, and prednisolone both the 17- and 21-hydroxy groups, and both molecules are effectively exported out of cells expressing ABCB1, with reduced intracellular accumulation and toxicity (Yates et al, 2003).


Antibiotics that are substrates of ABCB1 include:
gramicidin D (Lincke et al. 1990, Mechetner and Roninson 1992);
azithromycin (Munić et al. 2010);
erythromycin (Dey et al. 2004, Munić et al. 2010).

Literature References
PubMed ID Title Journal Year
20621639 Differences in assessment of macrolide interaction with human MDR1 (ABCB1, P-gp) using rhodamine-123 efflux, ATPase activity and cellular accumulation assays

Eraković Haber, V, Kelnerić, Z, Mikac, L, Munić, V

Eur J Pharm Sci 2010
20583968 P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice

Zhang, F, Zhuang, Y, Fraga, CH, Harstead, KE, Stewart, CF, Shen, J, Waters, CM, Panetta, JC, Schaiquevich, P, Tagen, M

Drug Metab Lett 2010
14661924 Structural determinants of P-glycoprotein-mediated transport of glucocorticoids

Swaan, PW, Schuetz, EG, Yates, CR, Yasuda, K, Chang, C, Dalton, JT, Miller, DD, Kearbey, JD

Pharm. Res. 2003
10484077 Profound differences in the transport of steroids by two mouse P-glycoproteins

Vo, QD, Gruol, DJ, Zee, MC

Biochem. Pharmacol. 1999
2898143 A retrovirus carrying an MDR1 cDNA confers multidrug resistance and polarized expression of P-glycoprotein in MDCK cells

Gottesman, MM, Lovelace, E, Pastan, I, Ueda, K, Rutherford, AV, Willingham, MC

Proc. Natl. Acad. Sci. U.S.A. 1988
9816258 Retroviral transfer of the human MDR1 gene confers resistance to bisantrene-specific hematotoxicity

Cardarelli, CO, Gottesman, MM, Pastan, I, Aksentijevich, I

Clin. Cancer Res. 1996
18282684 Inhibition of MDR1 expression by retinol treatment increases sensitivity to etoposide (VP16) in human neoplasic cell line

Castro, MA, Grivicich, I, Moreira, JC, Gelain, DP, Klamt, F, Passos, DT

Toxicol In Vitro 2008
2570070 Transepithelial transport of drugs by the multidrug transporter in cultured Madin-Darby canine kidney cell epithelia

Gottesman, MM, Chin, KV, Pastan, I, Williams, C, Handler, J, Horio, M, Goldenberg, S, Currier, SJ

J. Biol. Chem. 1989
3457471 Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification

Roninson, IB, Pastan, I, Chin, JE, Fojo, A, Shen, DW, Richert, N, Gottesman, MM

Science 1986
12379510 The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone

De Boer, AG, Meijer, OC, Karssen, AM, De Lange, EC, de Kloet, ER, van der Sandt, IC

J. Endocrinol. 2002
19862647 MDR1 polymorphism role in patients treated with cetuximab and irinotecan in irinotecan refractory colorectal cancer

Paule, B, Castagne, V, Farinotti, R, Adam, R, Guettier, C, Saffroy, R, Bonhomme-Faivre, L, Picard, V

Med. Oncol. 2010
15175422 Pharmacokinetics of erythromycin in rabbit corneas after single-dose infusion: role of P-glycoprotein as a barrier to in vivo ocular drug absorption

Mitra, AK, Gunda, S, Dey, S

J. Pharmacol. Exp. Ther. 2004
1968359 Multidrug resistance phenotype of human BRO melanoma cells transfected with a wild-type human mdr1 complementary DNA

Smit, JJ, Lincke, CR, van der Bliek, AM, Borst, P, van der Velde-Koerts, T, Schuurhuis, GJ

Cancer Res. 1990
9652413 Stoichiometry of coupling of rhodamine 123 transport to ATP hydrolysis by P-glycoprotein

Ling, V, Shapiro, AB

Eur J Biochem 1998
7865904 P-glycoprotein mediates profound resistance to bisantrene

Ho, JP, Greenberger, LM, Ritke, MK, Arceci, RJ, Zhang, XP, Slovak, ML, Durr, FE, Yalowich, JC, Annable, T, Collins, KI

Oncol. Res. 1994
1352877 Efficient inhibition of P-glycoprotein-mediated multidrug resistance with a monoclonal antibody

Mechetner, EB, Roninson, IB

Proc. Natl. Acad. Sci. U.S.A. 1992
12379217 Functional analysis of ABCA8, a new drug transporter

Fujimura, A, Wakaumi, M, Imai, M, Schwartz, GJ, Tsuruoka, S, Ishibashi, K, Suzuki, M, Yamamoto, H

Biochem Biophys Res Commun 2002
26208431 Temozolomide competes for P-glycoprotein and contributes to chemoresistance in glioblastoma cells

Scotto, KW, Rameshwar, P, Munoz, JL, Walker, ND

Cancer Lett. 2015
15899824 ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma

Waaga-Gasser, AM, Gasser, M, Huang, Y, Sadee, W, Schatton, T, Frank, NY, Frank, MH, Sayegh, MH, Margaryan, A

Cancer Res 2005
32981041 Is the emperor wearing shorts? The published structures of ABC transporters

George, AM, Jones, PM

FEBS Lett 2020
1356264 Partial purification and reconstitution of the human multidrug-resistance pump: characterization of the drug-stimulatable ATP hydrolysis

Cardarelli, CO, Gottesman, MM, Pastan, I, Lelong, IH, Ambudkar, SV, Zhang, J

Proc. Natl. Acad. Sci. U.S.A. 1992
10665657 Interaction of docetaxel ("Taxotere") with human P-glycoprotein

Tanigawara, Y, Okumura, K, Shirakawa, K, Komada, F, Sakaeda, T, Kasuga, M, Aoyama, N, Takara, K

Jpn. J. Cancer Res. 1999
12604685 Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux

Dai, H, Hayes, M, Marbach, P, Elmquist, WF, Lemaire, M

J. Pharmacol. Exp. Ther. 2003
23063411 Characterisation of the roles of ABCB1, ABCC1, ABCC2 and ABCG2 in the transport and pharmacokinetics of actinomycin D in vitro and in vivo

Brown, CD, Thomas, HD, Jamieson, D, Veal, GJ, Boddy, AV, Hill, CR

Biochem. Pharmacol. 2013
28132103 Polymorphisms in the multidrug-resistance 1 gene related to glucocorticoid response in rheumatoid arthritis treatment

Fritsch-Stork, RD, Lafeber, FP, Bijlsma, JW, Cuppen, BV, Yrlid, L, Marijnissen, AC, Kraan, MC, Pardali, K, Olsson, M

Rheumatol. Int. 2017
1359686 P-glycoprotein but not topoisomerase II and glutathione-S-transferase-pi accounts for enhanced intracellular drug-resistance in LoVo MDR human cell lines

Giannini, F, Toffoli, G, Tumiotto, L, Boiocchi, M, Sartor, F, Viel, A, Biscontin, G

Tumori 1992
15472518 Identification of budesonide and prednisone as substrates of the intestinal drug efflux pump P-glycoprotein

Schwab, M, Dilger, K, Fromm, MF

Inflamm. Bowel Dis. 2004
19447222 Influx and efflux transport as determinants of melphalan cytotoxicity: Resistance to melphalan in MDR1 overexpressing tumor cell lines

Brockmöller, J, Hagos, Y, Lage, H, Tzvetkov, MV, Burckhardt, G, Kühne, A

Biochem. Pharmacol. 2009
11504826 Kinetics of P-glycoprotein-mediated efflux of paclitaxel

Au, JL, Wientjes, MG, Jang, SH

J. Pharmacol. Exp. Ther. 2001
3472246 Expression of a full-length cDNA for the human "MDR1" gene confers resistance to colchicine, doxorubicin, and vinblastine

Gottesman, MM, Pastan, I, Ueda, K, Cardarelli, C

Proc. Natl. Acad. Sci. U.S.A. 1987
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ATPase-coupled transmembrane transporter activity of ABCA8/B1/B5 [plasma membrane]

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