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-canceragentsTransporters 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 ABCF1b. SLC Transporters Involved in Drug TransportIn 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/PAHS-070A.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