BREAST CANCER RESISTANCE PROTEIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 336

gall bladders and ligation of their common bile ducts and were then administered
intravenous PhIP. Levels of PhIP measured in the small intestine and cecum were
significantly higher in wild-type animals, confirming the efflux of the compound into
the lumen of the small intestine via Abcg2.
Adachi et al. 140 used both Abcg2 -deficient mice as well as hereditary hyperbiliru-
binemic mice deficient in Abcc2 to examine enterocyte efflux of substrates that have
been glucuronidated and sulfated in the liver prior to efflux into the intestinal lumen.
They found that Abcg2 had an important role in effluxing these conjugated metabo-
lites, and concluded that Abcc2 had a lesser role in effluxing some glucuronidated
conjugates.
12.9. GENETIC POLYMORPHISMS
Due to the potential pharmacologic impact, a number of studies have investigated
the impact that SNPs in the ABCG2 gene have on protein expression and function. A
number of SNPs have been identified in coding regions of the gene, and at least four
nonsynonymous SNPs have been identified. These SNPs occur at mRNA positions 34
(V12M; exon 2), 421 (Q141K, exon 16), 616 (I206L, exon 6), and 1768 (N590Y, exon
15). The V12M, I206L, and N590Y SNPs have not been found to confer an alteration
in protein expression or function. 141 , 142 However, the nonsynonymous substitution
C421A, in which a lysine is substituted for glutamine at amino acid (Q141K), has
been shown to have a functional significance. Various researchers have found that
this SNP can lead to lower plasma membrane expression, 141 , 143 − 145 reduced drug
efflux, 141 , 146 and reduced ATPase activity. 141 , 146 This polymorphism can lead to lower
IC 50 levels in cell lines exposed to cytotoxic agents that are ABCG2 substrates,
including mitoxantrone, irinotecan, and SN-38. 141 Additionally, when patients who
had the SNP were exposed to chemotherapy, higher in vivo levels of topotecan and
diflomotecan were found, 147 , 148 coinciding with the role of ABCG2 in biliary and
intestinal elimination of xenobiotics.
12.10. ABCG2 EXPRESSION IN CANCER AND ITS ROLE
IN DRUG RESISTANCE
Expression of ABCG2 in leukemia is by far the most extensively studied, a summary
of which is given in Table 12.2. In acute myelogenous leukemia (AML), conflicting
data exist regarding ABCG2 expression. Some groups have reported relatively high
ABCG2 expression, 149 − 151 whereas others reported undetectable levels. 152 − 154 Sim-
ilarly, ABCG2 has been found to be predictive of response to chemotherapy in some
studies 155 − 157 but not in others. 154 In acute lymphoblastic leukemia, a similar situation
exists, with ABCG2 reported to be predictive 158 , 159 and unpredictive 160 of response.
To clarify the contribution of ABCG2 to resistance in leukemia, more studies with
larger patient populations and validated methods are necessary. As discussed below,