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Drug Transport and drug target.pptx
1. PHARMACOGENETICS:
GENETIC POLYMORPHISM IN
DRUG TRANSPORT AND DRUG
TARGETS
Presented by :
Syeda Afreen Imtiaz(19115T0001)
Wardah Mineef Al Nahdi (19115T0003)
Mohd Ihtesham Ali Shah(19115T0005)
2. INTRODUCTION
Genetic polymorphism: It is the variations in DNA sequences. This
explains some of the variability in drug metabolizing enzyme activities
which contribute to alterations in drug clearance and impact patients
response to drug therapy.
3. • The completion of the human genome project resulted in the identification of
a large number of membrane-spanning proteins involved in endogenous
compound and drug transport which can be divided into two major groups.
• The first group includes members of the solute carrier(SLC) transporter
superfamily, which facilitate the influx and efflux of a wide range of
compounds without the use of ATP.
• The second major group of transporters are the multi-drug resistance (MDR)
are members of the ATP binding cassette (ABC) proteins which carry out
ATP-dependent drug efflux.
• Transporters are those proteins that carry either endogenous compounds or
xenobiotics across biological membranes.
• They can be classified into either efflux or uptake proteins, depending on the
direction of transport.
• The extent of expression of genes coding for transport proteins can have a
profound effect on the bioavailability and pharmacokinetics of various drugs.
4. • Additionally, genetic variation such as single-nucleotide polymorphisms (SNPs) of the transport
proteins can cause differences in the uptake or efflux of drugs.
• In terms of cancer chemotherapy, tumor cells expressing these proteins can have either enhanced
sensitivity or resistance to various anticancer drugs.
• Transporters that serve as efflux pumps on a cell membrane can remove drugs from the cell before they
can act.
• Transport proteins that are responsible for the vital influx of ions and nutrients such as glucose can
promote growth of tumor cells if overexpressed, or lead to increased susceptibility for a drug if the
transporter carries that drug into the cell.
• There are two superfamilies of transport proteins that have important effects on the absorption,
distribution and excretion of drugs:
1. ATP binding cassette (ABC) associated with MDR
2. Solute-carrier (SLC) superfamilies
5. The protein product of ABCC genes are commonly known as MRPs or multidrug
resistance proteins. They often transport anionic compounds.
Ten members of the MRP family are known and at least seven may be involved in
conferring resistance to cancer chemotherapeutics (MRP1-MRP7).
MRPs are located in various tissues with protective and excretory function such
as the brain, liver, kidney, and intestines.
MRP1 has the most likely significance in clinical anticancer drug resistance.
The MDR1 or ABCB1 gene codes for the efflux protein P-glycoprotein (P-gp)
that is frequently associated with drug resistance to antineoplastic agents
including vincristine and doxorubicin.
The ABCB1 gene codes for a glycosylated membrane protein originally detected
in cells that had developed resistance to cancer chemotherapy agents.
6. It is designated as a multidrug resistance protein due to the fact that its expression in a
cell may confer resistance to multiple classes of drugs with differing chemical structures
and mechanisms of action.
Besides being expressed in cancer cells, P-glycoprotein is expressed in multiple normal
tissues with excretory or protective function including intestine, kidney, liver, blood-
brain barrier, spinal cord, placenta.
P-gp has an important role in forming a protective barrier against absorption of
xenobiotics in these tissues.
The substrates for P-gp are often hydrophobic drugs with a polyaromatic skeleton and a
neutral or positive charge.
Functions of P-glycoprotein:
Function
Site of Transportation
Elimination
Liver - Bile
Excretion
Kidney - Urine
Protect fetal from drug
exposure
Placenta – Maternal blood
Reduce drug absorption into
the blood
Intestine – Intestinal Lumen
Monitor drug access to the
brain
Brain – Blood
7. The multidrug resistance-associated proteins (MRPs) are members of the ATP-binding
cassette (ABC) superfamily with six members currently, of which MRP1 (ABCC1), MRP2
(ABCC2), and MRP3 (ABCC3) are commonly known to effect drug disposition.
ABC transporters are present in cellular and intracellular membranes which can be
responsible for either importing or removing of substances from cells and tissues. They
often transport substances against a concentration gradient by using the hydrolysis of ATP
to drive the transport.
They are at least 49 ABC transporter genes, which are divided into seven different families
(A-G) based on sequence similarity.
Like MDR, these transporters can also be expressed in cancer cells, which confer
resistance to the chemotherapeutic agent tamoxifen.
It appears that polymorphism in this family are rare and occur at different frequencies
among different populations.
8. Solute Carrier Proteins
Solute carrier proteins (SLCs) are an important in transport of ions and organic substances across
biological membranes in the maintenance of homeostasis.
Examples of some of the endogenous solutes that are transported include steroid hormones,
thyroid hormones, leukotrienes, and prostaglandins.
The SLCs class includes the transporters known as the OATs (organic anion transporters), the
OATPs (organic anion transporting polypeptides) which are structurally different from OATs, the
OCTs (organic cation transporters), and PepTs (peptide transports).
SLCs are expressed in a variety of tissues such as liver, kidney, brain, and intestines.
Solute Carrier
ATP Binding Cassette
Influx/bidirectional
transporter
Efflux transporter
Electrochemical gradient/
facilitated diffusion
Utilize energy from ATP
Secondary active
Primary active
Subfamilies:
SLC15,SLC22,SLCO
Subfamilies:
ABCA,ABCB,ABCE,ABCD
F,ABCG
9. GENETIC POLYMORPHISM IN DRUG TARGETS
DRUG TARGETS:
Genetic polymorphisms occur commonly for drug target proteins, including receptors,
enzymes, ion channels, and intracellular signaling proteins.
Drug target genes may work in concert with genes that affect pharmacokinetic properties
to contribute to overall drug response.
11. RECEPTOR GENOTYPES AND DRUG RESPONSE
β1-Recptors are located in the heart and kidney, where they are involved in the regulation of
heart rate, cardiac contractility, and blood pressure. Two common nonsynonymous SNPs in
the β1-receptor gene are located at codons 49(Ser>Gly) and 389(Arg>Gly).
The influence of the β1-Recptors gene on blood pressure response to β1-Recptors blockade with
metoprolol.
Hypertensive patients who were homozygous for both the Ser49 and Arg389 alleles had greater
reductions in diastolic blood pressure with metoprolol monotherapy compared with carriers of the
Gly49 and / or Gly389 alleles.
12. β2-Receptors are located on bronchial smooth muscle cells, where they mediate bronchodilation upon
exposure to the β2-Receptors agonists.
Inhaled β2-agonists are the most effective agents for acute reversal of bronchospasms; however, the
magnitude of their effects varies substantially among asthmatic patients.
More than 11 SNPs have been identified in the β2-Receptor gene, 3 of which occur frequently and
result in amino acid changes.
Two common no synonymous SNPs are found in the genes coding block region, at codons 16 and 27,
and a third occurs upstream from the coding block in the genes promoter region.
13. ENZYME GENES AND DRUG RESPONSE
Vitamin K epoxide reductase(VKOR) is an example of an enzyme with genetic
contributions to drug response.
Warfarin exerts its anti-coagulant effects by inhibiting VKOR, thus preventing carboxylation
of clotting factor II, VII, IX, and X.
The vitamin k epoxide reductase complex subunit – 1 gene (VKORC1) encodes for VKOR.
Mutations in the VKORC1 coding region cause rare cases of warfarin resistance.
Carriers of these mutations either require exceptionally high warfarin doses(>100mg/wk) to
achieve effective anti-coagulation or fail to respond to any dose of warfarin.
14. GENES FOR INTRACELLULAR SIGNALING PROTEINS, ION CHANNELS, AND
DRUG RESPONSE
Cellular responses to many drugs are mediated through GTP binding proteins, also called G
proteins.
15. Disturbances in G-protein-mediated signal transduction have been implicated in the response to antidepressant
drugs.
A common SNP (C825T) occurs in the gene for the inhibitory G (Gi) protein β3- subunit and has been
associated with enhanced intracellular signal transduction.
The TT genotype has been correlated with greater improvement in depression symptoms among patients
treated with either a tricyclic anti-depressant or serotonin reuptake inhibitor, implying that the Gi protein β3-
subuint gene may have a role in therapeutic decision for depression management.
The Epithelial sodium channel (ENaC) is an example of an ion channel with genetic contribution to drug
response.
The ENaC is located in the distilled renal tubule and collecting duct of the nephron, where it serves as the final
site for sodium re-absorption.
The channel is composed of α -, β-, and γ-subunits. Mutations in the β- or γ-subunit cause excessive
sodium re-absorption and an inherited form of hypertension called Liddle syndrome.