Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Pharmacogenomics and Laboratory Medicine
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been shown that the ABCB1 C3435 allele, but not T/T genotype, significantly modulated
the concentrations of (R)-lansoprazole (a drug primarily used to treat ulcer and
acid reflux disease) in CYP2C19 EMs after renal transplantation (Li et al. 2014).
However, the clinical relevance of this observation may be minor because these
pharmacogenetic changes were not associated with the occurrence of gastroesophageal
complications. Therefore, the functional impact of the C3435T variant on the
pharmacokinetic and pharmacodynamic properties of ABCB1 substrates remains to
be defined.
Breast Cancer Resistance Protein
The human breast cancer resistance protein (BCRP) is the second member of the G
subfamily of the ATP-binding cassette (ABC) efflux transporter superfamily and is
therefore also known as ABCG2 (Ross et al. 1999). BCRP was originally discovered
in human breast cancer cell line MCF-7/AdrVp, which exhibited multidrug resistance
but had no expression of known multidrug efflux transporters such as ABCB.
In this breast cancer cell line, BCRP was overexpressed and resulted in multidrug
resistance to the chemotherapeutic agents, including mitoxantrone, topotecan, and
methotrexate, by transporting these compounds out of the cell. In addition to the
chemotherapeutic drugs, there are a wide variety of structurally and chemically
diverse compounds, including non-chemotherapy drugs transported by BCRP in an
ATP-dependent fashion. BCRP is highly expressed in various tissues, including the
small intestine, liver, brain endothelium, and placenta (Endres et al. 2006). In these
normal tissues, BCRP plays an important role in the absorption, elimination, and
tissue distribution of drugs. BCRP has been documented to be highly enriched in
a large number of stem cells of bone marrow and other organs, which is known
as side-population phenotype. BCRP may enhance cell survival in hypoxic condition
(hypoxia) by binding and interacting with heme to reduce the accumulation of
toxic heme metabolites. It has been recognized that cancer cells frequently show
side-population phenotype with expression of BCRP and other ABC family efflux
transporters to survive hypoxia and to avoid exposure to chemotherapeutic agents.
These subpopulations of so-called cancer stem cells are responsible for tumor selfrenewal
for many cancer types. Therefore, these ABC family efflux transporters may
contribute to drug resistance and eventually cancer cure failure.
The BCRP efflux transporter is encoded by the BCRP gene located at chromosome
4q22.1. BCRP transporter is highly polymorphic, with over 80 SNPs identified
in the BCRP gene. Some of these SNPs in the coding region of BCRP gene may
have significantly physiological and pharmacological relevance. The most important
BCRP variant is the C421A polymorphism (Imai et al. 2002), which causes a missense
mutation in the BCRP protein (Gln141Lys, or Q141K), resulting in low protein
expression and impaired transport activity, possibly due to increased lysosomal and
proteasomal degradations of this variant than wild-type BCRP (Giacomini et al.
2013). This variant is associated with interindividual difference in pharmacokinetics
and response or toxicity of many chemotherapeutic drugs. The frequency of C421A
is markedly different across ethnic groups, with 30–60% in Asians and 5–10% in
the white and black African Americans. Patients heterozygous for the BCRP C421A