MULTIDRUG RESISTANCE PROTEINS OF THE ABCC SUBFAMILY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 288

in intracellular substrate accumulation. For instance, 1-chloro-2,4-dinitrobenzene is
transported into the cell by basolateral uptake and conjugated with GSH to form DNP-
SG, which then inhibits the ABCC2-mediated efflux transport of BSP. 143 However,
inhibitors may not be selective for only one transport process, as exemplified by
cyclosporin A and the quinoline derivative MK571, which inhibit both the OATP1B3-
mediated uptake and the ABCC2-mediated efflux of CCK-8. 107
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
When one compares a pair of human chromosomes, a single nucleotide variant oc-
curs approximately every 1200 bp. 261 By March 2007, about 12 million of these
single-nucleotide polymorphisms (SNPs) had been compiled in the SNP database
of the National Center for Biotechnology Information (NCBI; http://www.ncbi.
nlm.nih.gov/SNP). Moreover, the International HapMap Consortium has generated
a haplotype map of the human genome by identifying more than 1 million SNPs
from 269 people of four different populations. 262 In this chapter we adhere to the rec-
ommendations of the Human Genome Variation Society (http://www.hgvs.org and
ref. 263) that a nucleotide or amino acid change should be designated as a sequence
variant rather than as a polymorphism or mutation, because the term mutation is used
ambiguously to indicate either a change or a disease-causing (pathogenic) change.
Similarly, the term polymorphism is used both to describe a non-disease-causing
(benign) change or a change found at a frequency of 1% or higher in the population.
For the nine human ABCC/MRP genes, several thousand single-nucleotide variants
are listed in the NCBI-SNP database. Whereas many sequence variants are present
in the introns and may have no phenotypic consequences at all, others are located
in the 5 - and 3 -flanking regions and may lead to an altered expression level of the
respective ABCC/MRP protein. Sequence variants within the exons, also designated
as coding SNPs (cSNPs), may result in amino acid substitutions. These nonsynony-
mous or missense variants are of considerable interest because they may affect the
transport function of the ABCC/MRP efflux pumps. The complete lack of a func-
tional protein may eventually lead to disease. Within the human ABCC subfamily,
sequence variants with functional consequences have been identified for ABCC2
(Dubin-Johnson syndrome, Section 11.7.1), ABCC6 (pseudoxanthoma elasticum,
Section 11.7.2), ABCC7 (cystic fibrosis, reviewed in ref. 264), ABCC8 (persistent
hyperinsulinemic hypoglycemia of infancy, reviewed in ref. 265), and ABCC9 (dilated
cardiomyopathy) 266 . Because the ABCC11 and ABCC12 genes have been mapped to
a region harboring the genes for paroxysmal kinesigenic choreoathetosis, both may
be candidate genes affected in this or in related neurological disorders. 25
At present, major research efforts are being taken to identify non-disease-
associated ABCC/MRP variants and to analyze their potential functional conse-
quences. Because ABCCs/MRPs function as drug efflux pumps (Section 11.4), these
variants may account for interindividual variation (e.g., in multidrug resistance, drug