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

108 Applying Pharmacogenomics in Therapeutics
interactions and environmental factors, genetic polymorphisms of drug transporters
have profound impacts on drug disposition, drug efficacy, and drug safety. Drug
transporters are categorized into two classes: efflux transporters, such as ABC superfamily
that pumps substrates out of the cell; and uptake or influx transporters, such
as OATP, which facilitate the entry of drugs into the cell. Here we discuss OATP and
two members of ABC transporters—ABCB1 and BCRP—to understand how such
drug transporters affect drug disposition, efficacy, and toxicity.
ABCB1
ATP-binding cassette subfamily B member 1 (ABCB1), also known as P-glycoprotein
(permeability glycoprotein, abbreviated as P-gp) or multidrug resistance protein 1
(MDR1), is an important protein of the cell membrane that transports many foreign
substances out of the cell. ABCB1 is extensively distributed and expressed in various
tissues, including the enterocytes, hepatocytes, and testis barrier. ABCB1 is an ATPdependent
efflux pump with a wide variety of substrate specificities, including many
important drugs such as colchicine and quinidine, the chemotherapeutic agents (such
as etoposide, doxorubicin, and vinblastine), immunosuppressive agents, and HIVtype
1 antiretroviral agents (such as protease inhibitors).
ABCB1 has many functions, one function of which is to regulate the distribution
and bioavailability of drugs. Increased intestinal expression of ABCB1 may decrease
the absorption of its substrate drugs, which results in reduced bioavailability and drug
plasma concentrations. In contrast, decreased intestinal ABCB1 expression may result
in supratherapeutic drug plasma concentrations and drug toxicity. Unfortunately,
some cancer cells also express large amounts of ABCB1, which makes these cancers
multidrug resistant due to active efflux transport of the antineoplastics out of the cell.
ABCB1 can also remove other toxic metabolites and xenobiotics from the cell into
urine, bile, and the intestinal lumen for excretion from the body.
The ABCB1 protein is encoded by the ABCB1 gene located at chromosome
7q21.12. ABCB1 is highly polymorphic, and some alleles exhibit ethnicitydependent
distribution. There are two frequently discussed ABCB1 SNPs: G2677T/A
(rs2033582, in exon 21) and C3435T (rs1045642, in exon 26) (Komar 2007). Both
SNPs have been examined for the association of the G2677T variant (also known as
Ser893Thr) with increased risk for developing lung cancer. In addition, the C3435T
variant may modulate this influence. Carriers of the 2677T/T plus heterozygous
3435C/T have the highest risk for developing lung cancer (up to 20-fold higher risk).
The G2677T/T allele frequency is greatly different across the ethnic groups, with
13% in the Asian population, 2% in the white population, and 0% in the African
population (Bournissen et al. 2009; Leschziner et al. 2007).
The SNP C3435T of ABCB1 is a synonymous polymorphism without alteration
in the amino acid. The frequency distribution varies across ethnic groups with the
highest homozygous seen in the white population (~26%), followed by the Asian
population (~17%), and the lowest in the black African population (~2.3%). There are
conflicting results on functional impact of the C3435T variant in the disposition of
the ABCB1 substrates. In one study, C3435T was shown as a “silent” polymorphism
in determining the substrate specificity (e.g., verapamil). On the other hand, it has