MULTIDRUG RESISTANCE PROTEINS OF THE ABCC SUBFAMILY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 264

11.5.6. ABCC6
11.5.7. ABCC10 to ABCC12
11.5.8. ABCC/MRP Efflux Pumps in Human Cancers
11.6. Double-Transfected Cells as a Model System to Study the Vectorial Transport
of Substances
11.6.1. Establishment and Characterization of Double-Transfected Cells
11.6.2. Functional Characterization of Double-Transfected Cells: Vectorial Transport
11.7. Sequence Variants of Human ABCC/MRP Genes and the Hereditary Deficiencies of
ABCC2 in Dubin-Johnson Syndrome and of ABCC6 in Pseudoxanthoma Elasticum
11.7.1. Hereditary ABCC2 Sequence Variants Causing Dubin-Johnson Syndrome
11.7.2. Hereditary ABCC6 Sequence Variants Causing Pseudoxanthoma Elasticum
11.7.3. Naturally Occurring Sequence Variants of ABCC1, ABCC3, ABCC4, and
ABCC5
11.8. Conclusions
References
11.1. INTRODUCTION
The absorption, distribution, and elimination of drugs is controlled decisively by
integral plasma membrane proteins. 1 The family of adenosine triphosphate (ATP)-
binding cassette (ABC) transporters includes a number of members that are located
in the plasma membrane and mediate the ATP-dependent efflux of endogenous and
xenobiotic substances. 2 Based on amino acid sequence similarity and phylogeny, the
48 known human ABC transporters are grouped into seven subfamilies designated
A through G. 2 Members of three ABC subfamilies have been recognized to play a
key role in drug efflux from cells: the MDR1 P-glycoprotein (ABCB1) of the ABCB
subfamily (discussed in Chapter 10), the breast cancer resistance protein (BCRP,
ABCG2) of the ABCG subfamily (discussed in Chapter 12), and the multidrug resis-
tance proteins (MRPs) of the ABCC subfamily (discussed in this chapter).
The human ABCC subfamily consists of 12 members: the nine MRPs as well as the
cystic fibrosis transmembrane conductance regulator (CFTR), and the two sulfonyl-
urea receptors SUR1 and SUR2. According to current topology prediction programs,
ABCC proteins have two cytoplasmic nucleotide-binding domains (NBDs) and, de-
pending on the isoform, two or three membrane-spanning domains (MSDs). The bind-
ing of ATP at the NBDs and subsequent ATP hydrolysis is required for ABCC/MRP-
mediated transport of substances across the plasma membrane. 3 ABCCs/MRPs
mediate the efflux of many endogenous and xenobiotic lipophilic organic anions,
and several have overlapping substrate specificities; some are also involved in
conferring resistance to a wide variety of chemotherapeutic and antiviral agents. 3 , 4
Their predominant localization in intestinal and renal epithelia, in hepatocytes, and