INTRODUCTION

The genetic codes for around 450 solute carriers (SLCs), also known as transporters¹, are present in the human genome and are prearranged into 52 families. Most of these transporters' biological functions are still unknown because not all of them have been thoroughly studied. Because mutations in more than 150 of the transporters have been linked to health problems, these transporters must play a specific biological role. The SLC22A family of organic cation transporters includes OCT1 (SLC22A1), OCT2 (SLC22A2), OCT3 (SLC22A3), OCTN1 (SLC22A4), OCTN2 (SLC22A5), and hCT2/OCT6 (SLC22A16)^2,3.

The ADME of cation compounds, such as food and medication, is carried out by these transporters. Despite having various affinities, OCT1, OCT2, and OCT3 all have overlapping substrate preferences⁴. Physiological routes are maintained through the functional interchangeability of these transporters. OCT1, OCT2, and OCT3 are expressed in varying degrees in various organs, including the brain, liver, small intestine, kidney, and small intestine^5,6. OCT1 is mostly articulated in the basolateral membrane of hepatocytes, which initiate the process of blood absorption; OCT2 is typically located in the basolateral membrane of kidney epithelial cells, and OCT3 is broadly dispersed throughout a range of organs. When OCTs are engaged in the trans-epithelial transport of a chemical, such as from the intestinal lumen to the blood, they are mostly connected to MATE efflux transporters throughout the epithelium^7,8. Although OCTs are likely to transport primarily endogenous substrates, it is believed that blocking the activity of these uptake transporters (UT) with the aid of potent inhibitors may be a useful tactic to halt the spread of cancer cells because it reduces their high energy requirement^9,10. Other studies are using a different approach, looking at how OCTs and other UTS are involved in the efficient absorption of anticancer drugs that would kill cancer cells^11-13. To increase drug entrance and quickly kill cancer cells, it may be necessary to raise UT countenance and activity in various circumstances. OCT1 downregulation has been linked to the emergence of hepatocellular carcinoma and cholangiocellular carcinoma following treatment with the anticancer drug sorafenib, according to recent studies¹⁴. This is evidence that OCT1 is necessary for drug absorption. Thus, by increasing OCT1 activity, sorafenib may be more readily absorbed by hepatocellular carcinoma patients¹⁵. Therefore, it is vital to identify each UT’s regulation, substrates, and inhibitor’s key strategies for getting rid of cancer cells. The fact that these transporters have a variety of substrates also means that additional elements, such as competition between nutrients and therapeutic drugs and polymorphisms that may alter the absorption of one substrate but not another, may also have an impact on their pharmacokinetics^16,17. Therefore, a full understanding of the composite and function of SLC22A members will result in a better understanding of how to make use of these UTs and increase their therapeutic potential^18,19. The OCT1 gene, also known as SLC22A1, is one of 298 genes that make up the ADME gene family, which contains proteins like transport, metabolizing enzymes, and transcription factors. This information is provided by the Pharma ADME Consortium^20,21. The remaining 266 OCT1 genes are categorized as extended genes, and the OCT1 gene is further separated into the 32 core ADME genes^22,23. Recent research by the International Transporter Consortium found that the OCT1 gene encodes a novel transporter, and it was recommended that this transporter be added as a target for current drug development and therapy. The substantial association between reactions to specific prescribed medications and genetic variants in OCT1 that modify function supports this assertion¹⁵. For instance, due to metformin's poor absorption into hepatocytes, many people with polymorphisms in the OCT1 gene respond poorly to the medicine.

The majority of what is known as “organic electrolytes"—a structurally diverse range of compounds that exhibit a negative charge (OAs), a positive charge (OCs), or both negative and positive charges at physiological pH are transported by SLCs from the SLC22, SLC44, and SLC47 families of transporters²⁴. This collection of compounds also includes xenobiotics relevant to pharmacology, toxicology, and other sciences, as well as endogenous molecules with physiological significance. Due to their charge at physiological pH, organic electrolytes require aided transport to traverse plasma membranes. Transporters that move OAs and OCs are found in both the ATP-binding cassette and SLC families of membrane transporters. However, in contrast to the ABC family's transporters, members of the SLC family operate through either facilitated diffusion or secondary active transport^6,25. Additionally, net flux is determined by the electrochemical gradients of the linked substrates. This research focuses on transport processes, the energy basis of directionality, substrate binding and translocation, and molecular control¹⁷. It primarily focuses on OA and OC exchangers that belong to the SLC22, 44, and 47 families²⁴. They have fixated a lot of attention on OA and OC transporters in recent years because of the knowledge that their activity has a significant impact on the ADME of drugs²⁶. The excretion of OAs and OCs by hepatocyte mechanisms involving SLC exchangers and renal tubule cells has a significant impact on the body's exposure to medications²⁷. SLC exchangers are prospective sites for drug interactions because polymorphisms in the genes training these transporters may result in changes in drug exposure and response. Understanding the molecular basis of OA and OC exchanger activity may facilitate the prediction of the role of these important transporters in drug exposure and response. Since these SLC family members have human orthologues, the authors limit, if possible, the discussion of specific kinetic or selective properties to them.

Structure of Oct:

The OCTs have 12 transmembrane spanning helices, expanded cytoplasmic loops between transmembrane alpha helices (TMHs) 6 and 7, and cytoplasmic N- and C-termini. They are structurally comparable to other major facilitator superfamily (MFS) proteins due to a few shared features. A lengthy extracellular loop between TMHs 1 and 2 and a particular sequence motif before TMH2 are two traits that set SLC22 members apart from other proteins²⁴. The human orthologs of OCT1, OCT2, and OCT3 have 554, 555, and 556 amino acid residues, respectively. The long cytoplasmic loop between the 6 and 7 and the cytoplasmic C-terminal region contain consensus sites for phosphorylation by protein kinase A, protein kinase C, protein kinase G, casein kinase 2, and/or calcium/clamouring-dependent protein kinase II. TMHs 1 and 2, the lengthy extracellular loop that connects OCT1 and OCT2, have six conserved cysteine residues and three N-linked glycosylation sites. These cysteines also have an impact on homo-OCT oligomer formation, proper folding, and trafficking and insertion into the plasma membrane. The conserved protein structure of additional MFS proteins appears to be shared by every member of the SLC22A family, including the OCTs: The 12 TMHs have pseudo twofold symmetry perpendicular to the membrane's plane and are arranged as N- and C-terminal bundles of six helices each²². Each bundle of helices has three inverted-topology repetitions of three consecutive helices, which is consistent with the "alternating access" mode of transport. Numerous families of transport proteins that are otherwise phylogenetically unrelated have this structural motif. MFS proteins form a water-filled gap surrounded by N-terminal amino acid residues between their N- and C-terminal regions. It is hypothesized that during ligand binding and substrate translocation, TMHs 1, 2, 4, and 5 as well as C-terminal TMHs 7, 8, 10, and 11 interact with cleft residues. Site-directed investigations led to the discovery of several "cleft" amino acids in OCTs that modify ligand binding and transport activity. These amino acids were used to build the homology models of OCT and OCT2, which were based on the structures of the MFS transporters LacY and GlpT, respectively. One of these, the highly conserved aspartate residue at position 475 in TMH 11, has a significant impact on ligand binding²⁸. These models also provide information on the structural basis of the different degrees of ligand selectivity of OCT1 and OCT2. Members of the OCT family, which range in length from 550 to 560 amino acids, have several structural similarities. For example, they have a unique membrane topology with twelve putative transmembrane spanning alpha helices, C- and N-termini inside the cell, an intracellular loop with phosphorylation sites between the sixth and seventh transmembrane domains, and a significant extracellular loop with glycosylation sites between the first and second transmembrane²⁹. The consensus sites for N-glycosylation at amino acid positions 71, 96, and 112 in the extracellular loop are highly conserved in the OCT2 mammalian orthologues³⁰.

Fig.1. Regulation of OCT activity

Functional Characteristics of Oct:

OCT1, OCT2, and OCT3 have similar basic transport appearances across a variety of species. First, a wide range of other compounds that are not transported block OCT1-3 while translocating a variety of organic cations with dramatically divergent chemical structures³¹. Most of the molecules carried by OCT1-3 are smaller than 4-A in diameter and have relative molecular weights of less than 500. Second, OCTs transport organic cations in an electrogenic manner. Electrogenicity of transport has been demonstrated for the human hOCT1 and hOC2 transporters as well as the rat transporters rOCT1, rOCT2, and rOCT3³². Third, OCTs act independently of Na+ and are independent of proton gradients when the effect of proton gradients on the membrane potential is taken into consideration. Fourthly, organic cations can be transported across the plasma membrane by OCTs in either direction. It has been demonstrated that rOCT1, rOCT2, hOCT2, rOCT3, and hOCT3 all exhibit cation efflux in addition to cation influx³³. Organic cations and weak bases that are positively charged at physiological pH make up most of the substrates carried by OCT transporters, while non-charged molecules can also be transported. The discovery that hOCT1 and hOCT2 transport prostaglandin E2 and F2, respectively, has not yet been able to be confirmed³⁴. The OCT-transporters' substrates include drugs, xenobiotics, endogenous compounds, and model substances. The model cation 1-Methyl-4-phenyl pyridinium is transported by OCT1, OCT2, and OCT3 from many species and has a high maximal uptake³⁵.

OCTs are systems that improve diffusion and enable the movement of electrogenic organic cations in both directions across the plasma membrane. The gradient in substrate concentration and the membrane potential act as the driving forces for cation translocation. Organic cations translocate at membrane potentials between -50 and -100 mV in the absence of an inorganic ion influx. It doesn't require a pH or electrochemical gradient between 6.5 and 9.0 units to function³⁶. Furthermore, unlike Na and Ca²⁺, OCT1 is not dependent on the co-transport of monovalent and divalent ions. However, membrane depolarization can be employed to reduce the transporter activity when the extracellular K concentration is increased³⁷. OCT1 is glycosylated in at least three places on the lengthy extracellular loop, like other SLC22 family members. OCT1's absence of glycosylation may result in it being absent from or less prevalent on the plasma membrane, which may limit its activity because glycosylation is essential for the transporter's trafficking to the plasma membrane. OCT1 also has a variety of potential phosphorylation-modifiable sites, which are used to regulate the transporter’s affinity swiftly and effectively for its substrates. For instance, protein kinases C and A may phosphorylate OCT1, altering the binding site's structure and raising OCT1's affinity for its substrate. When the Phosphor site database of post-translational modifications was analysed³⁸, it was discovered that OCT1 peptides were phosphorylated on the tyrosine residues Tyr361 and Tyr376. This information was gathered from investigations using tandem mass spectrometry in the discovery mode. These related Tyr240 and Tyr362 residues, along with Tyr377 and Tyr377, are phosphorylated by peptides produced from the related transporter OCT2. It has been shown that several tyrosine kinase inhibitors, can prevent the kinase from phosphorylating these residues by disrupting the transport function of OCT2 using the fluorescent substrate 4-4- [4- Dasatinib, a non-competitive tyrosine kinase inhibitor, is the most efficient tyrosine kinase inhibitor at low molar dosages in suppressing OCT2 function and has been approved as an oral Bcr-Abl and Src-family kinase inhibitor for the treatment of leukaemia. Based on the results for OCT2³⁹, it is feasible that a tyrosine kinase that phosphorylates Tyr361 and Tyr376 and is inhibited by the same tyrosine kinase inhibitors, particularly one that is most effective for OCT2, may also be positively controlling OCT1 activity. OCTs are used to electrochemically transport small organic cations with a variety of molecular configurations without the usage of sodium. These organic cations include poisonous toxins, naturally occurring substances, and drugs used for therapeutic purposes.

Recently, a few functionally relevant genetic variations in human OCT1 and hOCT2 were found. The functional characterization of genetic variants is unknown, even though the coding region polymorphisms of hOCT3 have already been identified. hOCT3, also known as extraneuronal monoamine transporter (EMT), is a cationic substrate transporter that is found in the kidney, liver, and placenta⁴⁰. It is involved in the cellular uptake and elimination of a variety of therapeutically important drugs as well as the inactivation of biogenic amines like catecholamines and histamines. The public single nucleotide polymorphism (SNP) database lists five non-synonymous SNPs for SLC22A3, but no functional analysis of these genetic variations has been done yet. In this study, the authors discussed the functional properties of the hOCT3 variants in transiently transfected cells. The whole cDNA for hOCT3 was retrieved, as was already indicated. The Quick-change Site-Directed Mutagenesis Kit was used to add point mutations to the hOCT3 cDNA in the appearance vector according to the manufacturer's instructions. Complementary oligonucleotides are introduced for mutagenesis. Each final sequence was checked using DNA sequencing⁴¹.

Substrates and inhibitors of OCT1:

A study of the literature and the human gene database, Gene Cards, revealed a wide range of substances that are allegedly OCT1 substrates. By using their high affinity for their ability to transport them, the archetypal chemical compounds 1-methyl-4-phenyl-pyridinium and tetraethyl ammonium, which are often used to classify UT into the organic cation transporter family, were used to identify OCT1⁴². Numerous endogenous chemicals, such as choline, polyamines, guanidine, histamine, epinephrine, adrenaline, noradrenaline, and dopamine, can be transported by OCT1 with varied affinities. Compared to polyamide, choline is more soluble in OCT1⁴³. These endogenous substrates can effectively compete for absorption with conventional substrates. OCT1 may also contain a variety of pharmaceuticals; these include.

· Quinine, which is used to treat malaria

· Anti-retroviral drugs like lamivudine, zalcitabine, pentamidine, and trimethoprim

· Metformin, Tropism, an anticholinergic hydrophilic quaternary amine used to treat overactive bladder syndrome

· The anticancer drugs imatinib Hepatocellular carcinomas can be treated with sorafenib, ovarian and acute myeloid leukaemia are among the deadly tumours that may be treated with anthracyclines, and chronic myeloid leukaemia is treated with imatinib⁴⁴.

The well-known characteristic of regulation is shared by many transporters, although there are many ways to use it. OCT is widely distributed in organs including the liver, kidney, and intestine that must deal with quickly varying levels of chemicals because of variable fluid and food intake as well as metabolic processes, therefore a rapid regulation of their function is both conceivable and desired. Numerous hormones that can activate a few regulatory pathways also have these organs as their targets. On the other hand, there are times when the body goes through considerable changes, such as during development or during disease states, which can potentially affect OCT countenance and result in protracted regulatory periods. It has been shown that different species or cell types may have different effects from the same pathway when it comes to the direct modulation of OCT transport. For instance, protein kinase (PKC) activation reduces tetraethyl ammonium (TEA) transport in isolated S2 segments of rabbit kidney proximal tubules while increasing OC transport in newly isolated collapsed human proximal tubules⁴⁵. However, because the tubules and cell culture models both contain a few organic cation transport channels, it is difficult to link these effects to a particular OCT-isoform. Understanding the control of several OCT isoforms has advanced significantly since the invention of cell culture techniques when cells were stably transfected with a single OCT isoform⁴⁶.

CONCLUSION:

Learning more about the molecular mechanisms by which OCT1 recognizes ligands and how this transporter promotes substrate translocation into cells is incredibly fascinating. The scientists predict that breaking down these basic principles could result in the creation of improved techniques for assessing the efficacy of various treatment plans. In silico modelling of the surfaces of the transporters' interactions with different ligands can give a general prediction of whether and how novel ligands would interact with the transporters, providing a basis for drug design and delivery. The specific amino acid residues that allow OCT1 to recognize a wide range of substrates are still unknown, even though many of the substrates have varied sizes and structures. since more and more evidence supports that. If one uptake transporter is altered, the appearance may change. Another is of interest to the authors. determining the potential effects of OCT1 depletion on other plasma membrane transporters. Furthermore, it is still unknown if OCT1 can overcome the challenge of directly transferring ligands onto DNA, such as anthracyclines.

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Received on 04.11.2022 Modified on 22.01.2023

Asian J. Research Chem. 2023; 16(3):205-210.

DOI: 10.52711/0974-4150.2023.00032