Reactome | ABCB1 transports xenobiotics out of the cell

ABCB1 transports xenobiotics out of the cell

Stable Identifier

R-HSA-9659680

Type

Reaction [transition]

Species

Homo sapiens

Compartment

plasma membrane, cytosol, extracellular region

ReviewStatus

5/5

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ABCB1 transports xenobiotics out of the cell

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The ATP-dependent translocase ABCB1 (also known as Multidrug resistance protein 1, or 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). ABCB1 is expressed in enterocytes and is highly abundant at the apical
(luminal) membrane, thereby limiting the intestinal uptake of many drugs (reviewed in Estudante et al., 2013). 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; International Transporter Consortium et al, 2010).

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 Munić, V, Kelnerić, Z, Mikac, L, Eraković Haber, 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 Tagen, M, Zhuang, Y, Zhang, F, Harstead, KE, Shen, J, Schaiquevich, P, Fraga, CH, Panetta, JC, Waters, CM, Stewart, CF	Drug Metab Lett	2010
14661924	Structural determinants of P-glycoprotein-mediated transport of glucocorticoids Yates, CR, Chang, C, Kearbey, JD, Yasuda, K, Schuetz, EG, Miller, DD, Dalton, JT, Swaan, PW	Pharm. Res.	2003
10484077	Profound differences in the transport of steroids by two mouse P-glycoproteins Gruol, DJ, Vo, QD, Zee, MC	Biochem. Pharmacol.	1999
2898143	A retrovirus carrying an MDR1 cDNA confers multidrug resistance and polarized expression of P-glycoprotein in MDCK cells Pastan, I, Gottesman, MM, Ueda, K, Lovelace, E, 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 Aksentijevich, I, Cardarelli, CO, Pastan, I, Gottesman, MM	Clin. Cancer Res.	1996
18282684	Inhibition of MDR1 expression by retinol treatment increases sensitivity to etoposide (VP16) in human neoplasic cell line Klamt, F, Passos, DT, Castro, MA, Gelain, DP, Grivicich, I, Moreira, JC	Toxicol In Vitro	2008
2570070	Transepithelial transport of drugs by the multidrug transporter in cultured Madin-Darby canine kidney cell epithelia Horio, M, Chin, KV, Currier, SJ, Goldenberg, S, Williams, C, Pastan, I, Gottesman, MM, Handler, J	J. Biol. Chem.	1989
22344233	Molecular pathways: regulation and therapeutic implications of multidrug resistance Chen, KG, Sikic, BI	Clin Cancer Res	2012
12379510	The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone Karssen, AM, Meijer, OC, van der Sandt, IC, De Boer, AG, De Lange, EC, de Kloet, ER	J. Endocrinol.	2002
19862647	MDR1 polymorphism role in patients treated with cetuximab and irinotecan in irinotecan refractory colorectal cancer Paule, B, Castagne, V, Picard, V, Saffroy, R, Adam, R, Guettier, C, Farinotti, R, Bonhomme-Faivre, L	Med. Oncol.	2010
23041352	Intestinal drug transporters: an overview Estudante, M, Morais, JG, Soveral, G, Benet, LZ	Adv Drug Deliv Rev	2013
11902585	Multidrug resistance in cancer: role of ATP-dependent transporters Gottesman, MM, Fojo, T, Bates, SE	Nat. Rev. Cancer	2002
15175422	Pharmacokinetics of erythromycin in rabbit corneas after single-dose infusion: role of P-glycoprotein as a barrier to in vivo ocular drug absorption Dey, S, Gunda, S, Mitra, AK	J. Pharmacol. Exp. Ther.	2004
1968359	Multidrug resistance phenotype of human BRO melanoma cells transfected with a wild-type human mdr1 complementary DNA Lincke, CR, van der Bliek, AM, Schuurhuis, GJ, van der Velde-Koerts, T, Smit, JJ, Borst, P	Cancer Res.	1990
2876781	Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells Chen, CJ, Chin, JE, Ueda, K, Clark, DP, Pastan, I, Gottesman, MM, Roninson, IB	Cell	1986
9652413	Stoichiometry of coupling of rhodamine 123 transport to ATP hydrolysis by P-glycoprotein Shapiro, AB, Ling, V	Eur J Biochem	1998
7865904	P-glycoprotein mediates profound resistance to bisantrene Zhang, XP, Ritke, MK, Yalowich, JC, Slovak, ML, Ho, JP, Collins, KI, Annable, T, Arceci, RJ, Durr, FE, Greenberger, LM	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
26208431	Temozolomide competes for P-glycoprotein and contributes to chemoresistance in glioblastoma cells Munoz, JL, Walker, ND, Scotto, KW, Rameshwar, P	Cancer Lett.	2015
32981041	Is the emperor wearing shorts? The published structures of ABC transporters Jones, PM, George, AM	FEBS Lett	2020
1356264	Partial purification and reconstitution of the human multidrug-resistance pump: characterization of the drug-stimulatable ATP hydrolysis Ambudkar, SV, Lelong, IH, Zhang, J, Cardarelli, CO, Gottesman, MM, Pastan, I	Proc. Natl. Acad. Sci. U.S.A.	1992
20190787	Membrane transporters in drug development Giacomini, KM, Huang, SM, Tweedie, DJ, Benet, LZ, Brouwer, KL, Chu, X, Dahlin, A, Evers, R, Fischer, V, Hillgren, KM, Hoffmaster, KA, Ishikawa, T, Keppler, D, Kim, RB, Lee, CA, Niemi, M, Polli, JW, Sugiyama, Y, Swaan, PW, Ware, JA, Wright, SH, Yee, SW, Zamek-Gliszczynski, MJ, Zhang, L	Nat Rev Drug Discov	2010
10665657	Interaction of docetaxel ("Taxotere") with human P-glycoprotein Shirakawa, K, Takara, K, Tanigawara, Y, Aoyama, N, Kasuga, M, Komada, F, Sakaeda, T, Okumura, K	Jpn. J. Cancer Res.	1999
12604685	Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux Dai, H, Marbach, P, Lemaire, M, Hayes, M, Elmquist, WF	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 Hill, CR, Jamieson, D, Thomas, HD, Brown, CD, Boddy, AV, Veal, GJ	Biochem. Pharmacol.	2013
28132103	Polymorphisms in the multidrug-resistance 1 gene related to glucocorticoid response in rheumatoid arthritis treatment Cuppen, BV, Pardali, K, Kraan, MC, Marijnissen, AC, Yrlid, L, Olsson, M, Bijlsma, JW, Lafeber, FP, Fritsch-Stork, RD	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 Boiocchi, M, Tumiotto, L, Giannini, F, Viel, A, Biscontin, G, Sartor, F, Toffoli, G	Tumori	1992
15472518	Identification of budesonide and prednisone as substrates of the intestinal drug efflux pump P-glycoprotein Dilger, K, Schwab, M, 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 Kühne, A, Tzvetkov, MV, Hagos, Y, Lage, H, Burckhardt, G, Brockmöller, J	Biochem. Pharmacol.	2009
11504826	Kinetics of P-glycoprotein-mediated efflux of paclitaxel Jang, SH, Wientjes, MG, Au, JL	J. Pharmacol. Exp. Ther.	2001
3472246	Expression of a full-length cDNA for the human "MDR1" gene confers resistance to colchicine, doxorubicin, and vinblastine Ueda, K, Cardarelli, C, Gottesman, MM, Pastan, I	Proc. Natl. Acad. Sci. U.S.A.	1987