Biomedical Engineering Reference
In-Depth Information
TABLE 11.5. (
Continued
)
Amino Acid
Effect Predicted
Experimentally Proven
NCBI-SNP
Substitution
a
by PolyPhen
b
ID
c
Functional Consequence
and/or Ref.
p.R1381S
Probably damaging
rs11568597
p.A1398V
Benign
rs11549764
p.G1423R
Probably damaging
202
p.A1513D
Benign
rs11656685
a
As recommended by the Human Genome Variation Society (http://www.hgvs.org/mutnomen) and by ref.
263, “p.” describes a change in relation to the deduced ABCC1 (NP 004987) or ABCC3 (NP 003777)
protein sequence.
b
PolyPhen online tool for assessing potential effects of amino acid substitutions, http://genetics.bwh.
harvard.edu/pph.
c
Single-nucleotide polymorphism database, http://www.ncbi.nlm.gov/SNP; data based on NCBI dbSNP
build 126, regular updates available.
quality control machinery, retained in the endoplasmic reticulum, and finally degraded
by proteasomes.
279
,
284
−
286
Some ABCC2 variants mature properly and are apically
localized but functionally inactive.
279
,
286
Abcc2 sequence variants have also been identified in two well-characterized hy-
perbilirubinemic rat strains, the GY/TR¯ rat
37
and the Eisai hyperbilirubinemic rat
(EHBR),
39
,
40
that are deficient in the secretion of anionic conjugates into bile. Based
on the molecular identification and cloning of rat Abcc2 as the apical conjugate efflux
pump, which is deficient in these rat strains,
41
,
42
,
287
both are considered to be animal
models of human Dubin-Johnson syndrome. Distinct sequence variants in the rat
Abcc2
gene leading to premature stop codons [i.e., at codon 401 (GY/TR
42
) and at
codon 855 (EHBR
287
)] result in the absence of the Abcc2 protein from the hepato-
cyte canalicular membrane.
33
,
41
,
42
Using an adenoviral expression system, the human
ABCC2
gene was introduced into the Abcc2-deficient EHBRs and resulted in synthesis
of human ABCC2 being localized in the hepatocyte canalicular membrane.
288
Human
ABCC2 was apparently functional in the biliary efflux of bilirubin glucuronosides,
because the conjugated hyperbilirubinemia, usually observed in the EHBRs,
39
,
40
was
largely reduced.
288
These rats may thus be used to study human ABCC2 function by
hepatobiliary elimination studies. Recently, several groups have generated and ex-
amined Abcc2 knockout mice
289
−
291
that appear to be healthy and fertile, similar to
Abcc2-deficient rats. Abcc2-deficient mice cross-bred with mice lacking other Abc
transporters will be useful to investigate the consequences when several of these efflux
pumps are deficient simultaneously.
Because ABCC2 contributes to the oral bioavailability of drugs as well as to the
hepatobiliary and renal elimination of drugs and anionic drug conjugates, ABCC2
variants with altered transport function may affect drug disposition in the body and
account for adverse drug reactions.
141
,
292
A number of naturally occurring nonsyn-
onymous sequence variants that do not cause Dubin-Johnson syndrome have been
identified whose functional consequences are currently unknown (refs. 6, 21, and 292-
295 and NCBI-SNP database). Most of them have low allele frequencies of 0.01 to
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