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Drug Transporter Gene

Transport proteins actively mediate the influx and efflux of drugs across cell membrane to
facilitate drug transport across the gastrointestinal tract, drug excretion into the bile and urine,
drug distribution across the bloodbrain barrier, and drug uptake into target cells. Genetic
variations for drug transport proteins may affect the distribution of drugs that are substrates
for these proteins and alter drug concentrations at their therapeutic sites of action. In general,
an efflux pump may mediate toxicity with pathways:
a. Reduced activity of the efflux pump may increase the oral bioavailabilty of the drug
and reduce renal and biliary excretion leading to increased plasma levelsfor a given
dose and possible dose-dependent adverse effects. Overactivity would thus have the
opposite effect and may lead to the need for increased dosage requirements.
b. Reduced activity at the level of the cell membrane may increase intracellular levels
because of reduced efflux and lead to toxicity of drugs, where the modeof toxicity
depends on intracellular accumulation, for example, anti-canceragents
Transporters group based on its highest expression in organ were:
a. in the intestine: HPT1, PEPT1, BCRP, MRP2, and MDR1
b. in the liver: OCT1, MRP2, OATP-C, NTCP and BSEP
c. In the kidney: OAT1 was expressed at the highest levels, followed by OAT3, OAT4,
MCT5, MDR1, MRP2, OCT2, and OCTN2
Transporters group based on its function were:
a. ABC Transporters Involved in Drug Transport
ABCA1
The ABCB1 (or MDR1) gene, the first ABC transporter identified. ABCB1 was
the first human ABC transporter gene cloned and characterized through its ability
to confer a multi-drug resistant (MDR) phenotype to cancer cells that had
developed resistance to certain chemotherapy drugs. It has been shown to
transport a wide range of hydrophobic substrates from diverse therapeutic classes,
including several anticancer drugs. ABCB1 is expressed in multiple healthy
organs, and is thought to play an important role in removing toxic substances or
metabolites from cells. For example, the protein is highly expressed in cells
comprising the bloodbrain barrier and presumably plays a role intransport of
toxic compounds out of the brain, effectively preventing uptake.
The expression of ABCB1 on the apical surface of epithelial cell of the lower
gastrointestinal tract (jejunum, ileum, and colon) has been shown to influence

intestinal drug absorption and limit oral bioavailability of a wide variety of


structurally diverse drugs, including important anticancer agents derived from

natural sources, though this is highly substrate dependent .


ABCG2
The ABCG subfamily consists of several half transporters that are generally
thought to form homo- or heterodimers to create the active transporter. (ABCG2,
also known as MXR, BCRP, or ABCP) that is comprised of one nucleotide
binding fold and one transmembrane region, often referred to as an NBF-TM.
ABCG2-mediated flux is primarily unidirectional, and it transports substrates
from the cytoplasm out of the cell.
The gene product ABCG2 has been shown to be a promiscuous transporter of a
large number of hydrophobic substrates, including several prescription drugs.
Similar to ABCB1, ABCG2 is expressed in apical membranes of multiple healthy
organs and thought to play an important role in removing toxic substances from
cells, in preventing excessive accumulation in certain tissues, and in reducing

absorption.
ABCA2, ABCA3, ABCA4, and ABCF1
b. SLC Transporters Involved in Drug Transport
In humans, there are more than 300 individual proteins that are organized into 47 families
of SLCs [75]. The SLC families encode membrane proteins that have been identified as
passive transporters, ion coupled transporters, and exchangers. Particular focus has been
applied to the organic anion transporting polypeptides (OATP) and the gene family that
encodes them, SLCO.
SLCO: SLCO1B1
OATP1B1 (OATP2, OATP-C, LST-1) is primarily expressed on the basolateral
membrane of hepatocytes in the human liver. Based on its localization and it
being an uptake transporter, the primary role of OATP1B1 is believed to be
removal of substrates from the blood into the liver. OATP1B1 represents a
mechanism underlying both drug-drug interactions due to competition at the
transporter and pharmacokinetic variation due to genetic polymorphisms in the

gene encoding the OATP1B1 protein, SLCO1B1.


SLCO: OATP1B3 (SLCO1B3)
Like OATP1B1, OATP1B3 (OATP8, LST-2) is predominantly expressed in the
basolateral membrane of hepatocytes in humans and transports a wide range of
structurally diverse compounds, with a certain degree of overlap in substrate
specificity between the two transporters.

SLCO: OATP1A2 (SLCO1A2), OATP2B1 (SLCO2B1), AND OTHER OATPS


OATP1A2 (OATP, OATP-A) is expressed in a wide variety of tissues. Similar to
other OATPs, a wide range of drugs and endogenous compounds have been found
to be either substrates for or inhibitors of OATP1A2. While several genetic
variants in the gene encoding OATP1A2, namely SLCO1A2, have been identified
in humans and several of these variants have been shown to cause functional
changes in vitro, no studies have yet evaluated any role that SLCO1A2 variants
may have in vivo on drug pharmacokinetics, efficacy, or toxicity.
Similar to OATP1A2, OATP2B1 (OATP-B), encoded by SLCO2B1, is expressed
in a variety of tissues, including liver, intestine, placenta, heart, and skin. Several
SLCO2B1 variants have been identified and have been associated with reduced
function in vitro, but no data is publicly available on any associations between

these variants and drug effects in vivo.


SLC38: SLC38A2, SLC38A5
SLC10: SLC10A1, SLC10A2.
SLC15: SLC15A1, SLC15A2.
c. Other Transporters Involved in Drug Transport
Vacuolar H+-ATPase: ATP6V0C
Copper Pumps: ATP7A, ATP7B
Aquaporins: AQP1, AQP7, AQP9
Major Vault Protein: MVP, and
Voltage-dependent Anion Channels: VDAC1 , VDAC2.

References:
Admin. 2012. Human Drug transporters PCR Array. Available online at:
http://www.sabiosciences.com/rt_pcr_product/HTML/PAHS070A.html#resource (Accessed on 15th March 2013)
Cavallari, L. H. and Y. W. Francis. 2012. Polymorphisms in Drug Transporter
Genes. Available online at:
http://accesspharmacy.com/content.aspx?
aID=7967024(accessed on 15th March 2013)
Franke, R.M., E.R. Gardner and A. Sparreboom. 2010. Pharmacogenetics of Drug
Transporters. Current Pharmaceutical Design. (16): 220-230.
Hilgendorf, C., G. Ahlin, A. Seithel, P. Artursson, A. Ungell and J. Karlsson. 2007.
Expression of Thirty-six Drug Transporter Genes in Human Intestine, Liver,
Kidney, and Organotypic Cell Lines. ASPET journal. (35: 8): 1333-1340.

Available online at: http://dmd.aspetjournals.org/content/35/8/1333.abstract


(Accessed on15th March 2013)

Compiled by:
Maratussholikhah Nurazizah
260110100154

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