This document summarizes transporter superfamilies in the human genome. It discusses the two main superfamilies - solute carrier (SLC) and ATP-binding cassette (ABC) transporters. The SLC superfamily includes 52 families and around 395 genes encoding mostly facilitative transporters. The ABC superfamily includes 7 families with 49 genes encoding active transporters that use ATP hydrolysis to transport substrates against gradients. Key transporters from these families play important roles in drug absorption, distribution, and elimination. Polymorphisms in various transporters have been associated with human diseases and drug interactions.

1. Transporter Superfamilies
in the Human Genome
Presenter: Akash Agnihotri

2. Introduction- Transporters
• Gate keeper of cells and organelles
• Proteins that carry either endogenous compounds or xenobiotics across
biological membranes
• They can be either efflux or uptake proteins, depending on direction of
transport
• Extent of expression of genes coding for transport proteins can have a
profound effect on bioavailability and pharmacokinetics of various drugs

3. Introduction- Transporters
• Transporters that serve as:
Efflux pumps- Can remove drugs from cell before they can act
Influx of ions and nutrients- Can promote growth of tumor cells if
overexpressed

4. Transporters in pharmacokinetics

5. Movement of drug across cellular
membrane
• To traverse cellular barriers (gastrointestinal mucosa, renal tubule, blood-
brain barrier, placenta) drug have to cross lipid membrane
Drug cross lipid membrane mainly
• Passive Diffusion transport
(Depend on lipid sol of drug)
• Carrier mediated transport
(require carrier)
• SLC- OCT,OAT
• ABC- P-gps

6. Superfamilies of transport proteins
• 2 superfamilies of transport proteins:
Solute- carrier (SLC)
Superfamilies
ATP- binding cassette (ABC)
Superfamilies
 49 genes- classified into 7 families
 Primary Active Transport
 52 families with 386 Transporters
 Secondary Active Transport

7. SLC Gene Nomenclature System
SLC 3 A 1
Solute Like
Carrier
(Root symbol)
Solute Carrier
Family here, 3
Subfamily here, A
(Not subdivided)
Individual Transporter
Gene here, 1

8. SLC Gene Nomenclature System
• A few exceptions exist within the SLC series:
• SLC51 family- Consists of 2 members (SLC51A and SLC51B) that are not
related by sequence similarity but instead encode the two subunits (alpha
and beta) of organic solute transporter
• Another SLC21 organic anion transporter family which now uses root
symbol SLCO

9. SLC Gene Nomenclature System
• Indeed, SLC series originally developed for human genes
• But some SLC series found in rodents- Slc7a12 and multiple members of
SLC22 family
• Even in insects- slc18a4 identified in Drosophila and honey bee

10. Solute Carrier Proteins (SLCs)
• Located in the cell membrane
• SLC superfamilies includes 52 families
• Represents about 395 genes in human genome
• Solute carrier proteins (SLCs) are important in transport of ions and
organic substances across biological membranes in maintenance of
homeostasis

11. SLC Transporters
• Myriad substrates, including inorganic and organic ions, interact with SLC
transporters
• Highly selective transporters - interact with structurally similar molecules
e.g., Transporters in the SLC18 family - interact with monoamines
• Transporters that accept a broad range of chemically diverse substrates
e.g., Organic ion transporters in the SLC22 family
• Unlike ABC, SLC transporters are mostly facilitative transporters

12. The SLC Superfamily

13. The SLC Superfamily

14. Functions of SLC transporters
• SLC1, SLC3, SLC6, SLC7, SLC25, and SLC36 families
Intestine and kidney, among other organs, transport an array of amino acids critical
in protein synthesis and energy homeostasis
• Glucose and other sugars interact SLC2, SLC5, and SLC50 families for
absorption, elimination, and cellular distribution
• SLC11, SLC30, SLC39, and SLC40 families transport- zinc, iron, and other
metals
• SLC19, SLC46, and SLC52 families transport- water-soluble vitamins
• SLC6 move neurotransmitters across the plasma membrane
• SLC18 family members transport neurotransmitters into storage vesicles

15. SLC transporters and diseases
• Over 100 SLC transporters associated with monogenic disorders
• Many SNPs reached a genome-wide level of significance in association
studies of human disease
• Examples-
• Polymorphisms in SLC30A8 are associated with type 1 diabetes
mellitus
• Polymorphisms in SLC22A4 and SLC22A5 are associated inflammatory
bowel disease

16. SLC types of transporters
• Solute carrier protein class includes the transporters:
• Organic Anion Transporters (OATs)
• Organic Anion Transporting Polypeptides (OATPs) which are structurally
different from OATs
• Organic cation transporters (OCTs)
• Peptide Transport Proteins (PepTs)

17. OAT Family
• Organic Anion Transporter family (SLC22A)
• Primary function - Removal of xenobiotics from body & toxins
(Ochratoxin)
• Mainly expressed in the kidneys (PCT)
• Uptake of-
• Small org anions (conjugated steroids, biogenic amines & cGMP)
• Broad range of xenobiotics (antivirals, antibiotics, ACE inhibitors & anti
Ca drugs)

18. OAT Family- Example
• OAT 4 & URAT 1 ( Urate Anion Transporter)- mediate uric acid
reabsorption
• Inhibitors (eg. Probenecid - URAT1 inhibitor)
↓
↓ uric acid absorption
↓
↓ blood uric acid levels
↓
Therapeutic benefit in Rx of gout

19. Inhibition of hepatic OATPs
(Drug interactions involving hepatic transporters)
• Cyclosporine, Gemfibrozil, Lopinavir/Ritonavir
↓
Inhibit OATPs
↓
Inhibit hepatic uptake of statins
↓
↑ BA of statins

20. OCT Family
• Organic Cation Transporter family (SLC22A family)
• Primary function - removal of xenobiotics from body (eg. PPIs, metformin,
procainamide etc) & toxins (eg. Nicotine)
• Transport of small org cations like – catecholamines, hormones &
neurotransmitters (Ach, monoamines)
• Passive transporters
• Can be bidirectional

21. SLCs Important Transporters:
Transporters Gene Name Tissue
Localization
Substrate
Serotonin
Transporter
SLC6A4 Neurons, Heart
Valve
Serotonin
Reductase folate
carrier (RFC-1)
SLC19A1 Kidney, leukemic
cells
Methotrexate,
Leucovorin
OATP1B1 SLOC1B1 Liver, Brain Pravastatin
Digoxin
OATP1B3 SLOC1B3 Liver Methotrexate
PEPT1 & PEPT2 SLC15A1
SLC15A2
Small intestine
(PEPT1)
Broad distribution
(PEPT2)
Cephalexin, other
Beta-lactam
antibiotics, ACE
inhibitor

22. The ABC Superfamily

23. ABC Transporter Nomenclature System
ABC A 1
ATP- Binding
Cassette
Subfamily
here, A
Subfamily
member, 1

24. The ABC Superfamily
• They often transport substances against a concentration gradient by using
hydrolysis of ATP to drive transport
• 49 ABC transporter genes- 7 different families (A-G) based on sequence
similarity
• Responsible for either importing or removing of substances from cells and
tissues
• Mutations in 13 of the genes for ABC transporters cause or contribute to
human genetic disorders

25. Human ABC Superfamily

26. Human ABC Superfamily
• Three of these seven gene families are particularly important for drug
transport and multiple drug resistance in tumor cells:
• ABCB1 gene, encoding MDR1 (also known as P-glycoprotein)
• ABCG2 (Breast cancer resistance protein)
• ABCC family (ABCC1 through ABCC6) or multidrug resistance proteins
(MRP)

27. ABCB1 Transporters
• ABCB1 gene codes for a glycosylated membrane protein originally
detected in cells that had developed resistance to cancer chemotherapy
agents
• Protein is commonly referred to as Pglycoprotein (P-gp) or multidrug
resistance protein-1 (MDR1).
• Multidrug resistance/ Transporters associated with antigen processing
(MDR/TAP)
• 11 members
• P-glycoprotein (MDR1/ABCB1) - expressed in cancer cells- multidrug
resistance

28. Drug interactions with P-gp:
Inhibitors: Cyclosporine A, Quinidine & Ritonavir
↓
↑ intestinal uptake & ↓ biliary & renal excretion of digoxin
↓
↑ plasma levels of digoxin

29. ABCC Transporters
• Protein product of ABCC genes are commonly known as MRPs or
multidrug resistance proteins
• MRPs 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 to
MRP7)
• MRP1 has the most likely significance in clinical anticancer drug resistance
• MRPs are located in various tissues with protective and excretory function
such as the brain, liver, kidney, and intestines

30. ABCG Transporters
• ABCG2 is alternatively known as Breast Cancer Resistance Protein (BCRP),
placenta-specific ABC transporter (ABCP)
• Very important in limiting bioavailability of certain drugs
• Highly expressed in gastrointestinal tract, liver, and placenta
• Influences absorption and distribution of a wide variety of drugs
• Substrates- Doxorubicin, daunorubicin, estrogen sulphate and topotecan

31. Tissue Distribution of Drug-Related
ABC Transporters
• MDR1 (ABCB1), MRP2 (ABCC2), and BCRP (ABCG2) apical side of intestinal
epithelia
function- pump out xenobiotics, including many orally administered drugs
• MRP3 (ABCC3)- Basal side of the epithelial cells
• MDR1, MRP2, BCRP, and MRP4 (ABCC4)- Border membrane of renal
epithelia
• MDR1, MRP2, and BCRP- Bile canalicular membrane of hepatocytes
• MRP3 and MRP4- sinusoidal membrane of hepatocytes

32. ABC transporters form barriers
• BBB- MDR1 and MRP4
• Blood-CSF barrier- MRP1 and MRP4
• Blood-testis barrier- MRP1 and MDR1
• Blood-placenta barrier- MDR1, MRP2, and BCRP

34. ABC Transporters in Drug Absorption
and Elimination
• Systemic exposure to orally administered digoxin is decreased by
coadministration of rifampin (an MDR1 inducer)
• MDR1 expressed on brush border membrane of renal epithelia, and its
function can be monitored using digoxin (> 70% excreted in the urine)
• MDR1 inhibitors (e.g., quinidine, verapamil, spironolactone,
clarithromycin, and ritonavir) all markedly reduce renal excretion of
digoxin
• Clinical significance- Drugs with narrow therapeutic windows (e.g.,
digoxin, cyclosporine, tacrolimus) should be used with great care if MDR1-
based drug-drug interactions are likely

35. References
1. Goodman LS. Goodman and Gilman's the pharmacological basis of
therapeutics. New York: McGraw-Hill; 2018.
2. Flower RJ, Henderson G, Loke YK, MacEwan D, Rang HP. Rang & Dale's
Pharmacology E-Book. Elsevier Health Sciences; 2018 Nov 4.
3. Hediger MA, Clémençon B, Burrier RE, Bruford EA. The ABCs of
membrane transporters in health and disease (SLC series): introduction.
Mol Aspects Med. 2013 Apr-Jun;34(2-3):95-107. doi:
10.1016/j.mam.2012.12.009. PMID: 23506860; PMCID: PMC3853582
4. Basic and Clinical pharmacology, 13th edition by B.G. Katzung
5. https://www.genenames.org/data/genegroup/#!/group/805

36. Thank you