ATP Binding Cassette Transporters

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Several members of the ATP binding cassette (ABC) transporter protein super-family have been shown to impart multidrug resistance by virtue of their ability to efflux xenobiotics from the cytoplasm and across the cellular membrane in an energy-dependent, polarized manner. These various ABC transporter superfam-ily isoforms constitute a broad array of substrate specificities from endogenous fatty acid metabolites to synthetic therapeutics. A common characteristic shared by ABC transporters is the presence of nucleotide binding domain(s) (NBDs),

Figure 7.1. Transmembrane arrangement of drug transporter proteins. (A) is the schematic of P-gp (MDR1), MDR3, MRP4, MRP5, and MRP8 that have 12 TM (transmembrane) regions and two NBDs (nucleotide binding domains), (B) shows the MRP transporters (MRP1, MRP2, MRP3 and MRP6, and MRP7) that has five extra TM regions toward the N terminus. (C) depicts the BCRP that has six TM regions and one NBD also called as a half transporter

Figure 7.1. Transmembrane arrangement of drug transporter proteins. (A) is the schematic of P-gp (MDR1), MDR3, MRP4, MRP5, and MRP8 that have 12 TM (transmembrane) regions and two NBDs (nucleotide binding domains), (B) shows the MRP transporters (MRP1, MRP2, MRP3 and MRP6, and MRP7) that has five extra TM regions toward the N terminus. (C) depicts the BCRP that has six TM regions and one NBD also called as a half transporter which enable these integral membrane proteins to hydrolyze ATP to drive efflux (Fig. 7.1) (Higgins, 1991).

The cloning of the human genome, coupled with various genomic and functional studies, has revealed 49 human ABC transporter isoforms that are separated into seven distinct subfamilies based on their sequence homology (ABCA to ABCG). A complete description concerning the various ABC transporter subfamilies can be found at the Web site http://www.gene.ucl.ac.uk/nomenclature/ genefamily/abc.html. Among these subfamilies, the ABCB and ABCC subfamilies contain the most widely investigated transporters influencing human intestinal absorption. Specifically, P-glycoprotein (ABCB1, P-gp) and multidrug resistance-associated proteins (ABCC, MRPX) have not only been shown to be expressed along the Gi tract, but due to their cellular localizations and broad substrate specificities, appear to be the primary efflux pumps determining xenobiotic absorption (Table 7.1). The ABCG2 isoform, also known as the breast cancer resistance protein (BCRP), has also been demonstrated to affect the intestinal absorption of various therapeutic agents. The molecular and functional characteristics of these isoforms on the intestinal absorption of drugs are discussed more comprehensively below.

Table 7.1. Classification details of the important influx and efflux transporters present in the human small intestine. The table has been summarized from the information obtained from HUGO (Human Genome Organization) gene nomenclature committee's Web site (http ://www. gene.ucl. ac.uk/nomenclature/)_

Table 7.1. Classification details of the important influx and efflux transporters present in the human small intestine. The table has been summarized from the information obtained from HUGO (Human Genome Organization) gene nomenclature committee's Web site (http ://www. gene.ucl. ac.uk/nomenclature/)_

General name

Other names

Approved gene symbol

Gene name

Location

Sequence accession IDs

P-glycoprotein (P-gp)

CD243 GP170 ABC20

ABCB1

ATP-binding cassette, sub-family B (MDR/TAP), member 1

7q21.1

M14758 NM.000927

Sister of P-gp (sP-gp)

ABC 16 PFIC-2 PGY4

ABCB11

ATP-binding cassette, sub-family B (MDR/TAP), member 11

2q24

AF091582

Multidrug resistance related

GS-X

ABCC1

ATP-binding cassette, sub-family

16pl3.1

L05628

proteins 1 (MRP1)

C (CFTR/MRP), member 1

Multidrug resistance related

DJS cMRP

ABCC2

ATP-binding cassette, sub-family

U63970

proteins 2 (MRP2)

C (CFTR/MRP), member 2

Multidrug resistance related

cMOAT2

ABCC3

ATP-binding cassette, sub-family

17q21

Y17151

MLP2

MOAT-D

C (CFTR/MRP), member 3

NM.020038

Multidrug resistance related

MOAT-B

ABCC4

ATP-binding cassette, sub-family

13q31

U66682

proteins 4 (MRP4)

C (CFTR/MRP), member 4

Multidrug resistance related

S MRP, MOAT-C

ABCC5

ATP-binding cassette, sub-family

3q27

AF 104942

proteins 5 (MRP5)

C (CFTR/MRP), member 5

NM.005688

Multidrug resistance related

EST349056,

ABCC6

ATP-binding cassette, sub-family

16pl3.1

X95715

proteins 6 (MRP6)

MLP1

C (CFTR/MRP), member 6

Breast cancer resistance protein

MXRABCP

ABCG2

ATP-binding cassette, sub-family G (WHITE), member 2

4q22-q23

AF 103796

Peptide transporter 1 (PEPT1)

SLC15A1

Solute carrier family 15 (oligopeptide transporter), member 1

13q33-q34

(continued)

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Table 7.1.

(Continued)

General name

Other names

Approved gene symbol

Gene name

Location

Sequence accession IDs

Peptide histidine transporter 1

PTR4

SLC15A4

Solute carrier family 15,

12q24.32

AY038999

(PHT1)

member 4

NM.145648

Peptide histidine transporter 1

hPTR3

SLC15A3

Solute carrier family 15,

1 lql2.2

AB020598

(PHT2)

member 3

NM.016582

Concentrative nucleoside

SLC28A1

Solute carrier family 28

15q25-26

U62967

transporter (CNT1)

(sodium-coupled nucleoside transporter), member 1

Concentrative nucleoside

SPNT1 HCNT2

SLC28A2

Solute carrier family 28

15ql5

U84392

transporter (CNT2)

HsT17153

(sodium-coupled nucleoside transporter), member 2

NM.004212

Monocarboxylate transporter

SLC16A1

Solute carrier family 16

lpl2

BC026317

(MCT1)

(monocarboxylic acid transporters), member 1

NM.003051

Organic Cation transpoter

SLC22A1

Solute carrier family 22 (organic

6q26

U77086

(OCT1)

cation transporter), member 1

Organic anion transporting

SLCOIBIO

SLC21A6

Solute carrier organic anion

12pl2

NM.006446

polypeptide (OATP1B1)

ATP-C LST-1

transporter family, member 1B1

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