Organic Cation Transporters
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Organic Cation Transporters
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Author : Giuliano Ciarimboli
language : en
Publisher: Springer
Release Date : 2015-12-17
Organic Cation Transporters written by Giuliano Ciarimboli and has been published by Springer this book supported file pdf, txt, epub, kindle and other format this book has been release on 2015-12-17 with Medical categories.
This innovative text explores the cellular transport of organic cations, from functional and structural properties to pharmacological implications and psychiatric developments. The authoritative chapters introduce organic cation transporters and then proceed to discuss their mechanisms such as binding of substrates and inhibitors; their drug dispositions and toxicity; their relationships to genetic and pathophysiological variability; and their roles in endocrine, metabolic, and neurological systems. The final chapters delve into the use of animal models for the study of organic cation transporter function and their possible use in environmental cycling of pharmaceutical residues. This comprehensive volume unites integrative transporter physiology with structural and molecular biology, genetics, pharmacology and pathophysiology, offering a holistic approach to utilizing this novel technique in physiological contexts. It will prove invaluable reading for researchers and students in various areas of integrative, organ, cell and molecular physiology as well as pharmacologists and neurologists.
Organic Cation Transporter 1 Oct1 Not Vital For Life But Of Substantial Biomedical Relevance
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Author : Jurgen Brockmoller
language : en
Publisher: Frontiers Media SA
Release Date : 2022-01-12
Organic Cation Transporter 1 Oct1 Not Vital For Life But Of Substantial Biomedical Relevance written by Jurgen Brockmoller and has been published by Frontiers Media SA this book supported file pdf, txt, epub, kindle and other format this book has been release on 2022-01-12 with Science categories.
Around one third of all biologically relevant small molecules are organic cations. These include endogenous substances like catecholamines and other neurotransmitters, toxins and drugs designed to affect signaling processes. The organic cation transporter 1 (OCT1) is among the strongest expressed membrane transporters at the sinusoidal (blood-facing) side of liver cells and contributes substantially to the clearance of the blood from numerous organic cations. A most striking feature of OCT1 is its pronounced genetic diversity. Between 1 and 10% of all human populations have little to no OCT1 activity. With several of the OCT1 substrates up to 10% of Europeans are functionally OCT1 deficient. Apparently, the lack of OCT1 do not lead to apparent substantial pathological changes in these individuals. It thus appears that this transporter is not essential to human life, but does it means that OCT1 is irrelevant? In the last 25 years since the first cloning of this transporter, data on its pharmacological and physiological relevance is steadily accumulating. Numerous clinically relevant drugs (e.g. metformin, morphine, fenoterol, sumatriptan, tramadol and tropisetron) have been shown to be substrates of OCT1, and OCT1 deficiency has been shown to affect the pharmacokinetics, efficacy, or toxicity of these drugs. Also vitamin B1 has been shown to be a substrate of OCT1, and in genetically modified mice OCT1 substantially modulated hepatic lipid metabolism, total body fat and systemic glucose and lipid concentrations. Still, numerous important questions remain unsolved: For which drugs, toxins, or other endogenous or exogenous substances is OCT1 relevant? How can we predict the relevance of OCT1 from in vitro studies? What determines the substrate selectivity of OCT1 in comparison to other transporters or transport processes for organic cations? What regulates the expression of OCT1 in the liver and possibly in other tissues? What is the impact of OCT1 variation in different areas of medicine, including the therapies for cancer as well as for pulmonary, cardiovascular, or neurological diseases? How can evolutionary biology contribute to a better understanding of the roles of OCT1? And, importantly, what types of research are likely to significantly further the knowledge on OCT1 in the next decades?
Organic Cation Transporters In The Central Nervous System
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Author : Lynette C. Daws
language : en
Publisher: Springer Nature
Release Date : 2021-10-27
Organic Cation Transporters In The Central Nervous System written by Lynette C. Daws and has been published by Springer Nature this book supported file pdf, txt, epub, kindle and other format this book has been release on 2021-10-27 with Medical categories.
Rapidly growing interest in the role of organic cation transporters (OCTs) and plasma membrane monoamine transporter (PMAT) in central monoamine homeostasis makes this book especially timely, given its thematic alignment with the role of OCTs and PMAT in CNS. This book discusses latest insights into the field laying an emphasis on health, disease and therapeutics. The chapter, “General Overview of Organic Cation Transporters in Brain”, of this book is available open access under a CC BY 4.0 license at link.springer.com
Organic Cation Transport
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Author : Giuliano Ciarimboli
language : en
Publisher:
Release Date : 2007
Organic Cation Transport written by Giuliano Ciarimboli and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2007 with Carrier proteins categories.
Physiology Biochemistry And Pharmacology Of Transporters For Organic Cations
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Author : Giuliano Ciarimboli
language : en
Publisher: MDPI
Release Date : 2021-06-24
Physiology Biochemistry And Pharmacology Of Transporters For Organic Cations written by Giuliano Ciarimboli and has been published by MDPI this book supported file pdf, txt, epub, kindle and other format this book has been release on 2021-06-24 with Medical categories.
Membrane transporters are of vital importance for cells. They mediate the flux of many substances through the plasma membrane. In this book, the transporters for organic cations, a special class of membrane transporters, are presented. Transporters belonging to this class are important because they allow many neurotransmitters (e.g., histamine and serotonin) and many drugs (e.g., trospium and tofacitinib) to permeate the plasma membrane. Therefore, transporters for organic cations can modulate the action of neurotransmitters and drugs, having in this way important physiological and pharmacological implications. These aspects are illustrated in original works and reviews presented in this book. Using a system biology approach, the global significance of different transporters working together has been illustrated. Regulation mechanisms determining their expression in specific organs and modulating their function are also described in this book, also concerning their role for special drug toxicities. Such an aspect is also discussed in relationship to mutations (single nucleotide polymorphisms) of transporters for organic cations. Finally, the translational value of studies performed in flies, mice, and rats is discussed. Therefore, this book offers integrative information on transporters for organic cations, which may be of interest to beginners and specialized scientists in this field.
Role Of Organic Cation Transporters In Cadmium Transport
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Author :
language : en
Publisher:
Release Date : 2011
Role Of Organic Cation Transporters In Cadmium Transport written by and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2011 with Cadmium categories.
Molecular Mechanisms Of Organic Cation And Anion Transporters
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Author : Mark Jason Dresser
language : en
Publisher:
Release Date : 2000
Molecular Mechanisms Of Organic Cation And Anion Transporters written by Mark Jason Dresser and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2000 with Carrier proteins categories.
Contribution Of Membrane Transporters To The Disposition Of Organic Cations
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Author : Muhammad Erfan Uddin
language : en
Publisher:
Release Date : 2022
Contribution Of Membrane Transporters To The Disposition Of Organic Cations written by Muhammad Erfan Uddin and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2022 with Biological transport categories.
Membrane transporters play a pivotal role in maintaining cellular integrity via the removal of toxic metabolites or entry of essential nutrients. Despite regulating cellular influx and efflux, tissue-specific expression of transporters contributes to local drug accumulation and drug-drug interactions (DDIs), and functional alterations in these transporters can directly influence an individual’s susceptibility to drug-induced toxicity. Here, we provide an overview of membrane transporters with a role in drug-induced toxicity and discuss novel strategies to improve therapeutic outcomes. We highlighted the contribution of membrane transporters in chemotherapy-induced various toxicities (Chapter 1). We then evaluated in vitro and in vivo functional regulation of organic cation transporter 1 (OCT1), a most abundant cationic transporter expressed in the liver, and identified an OCT1 specific biomarker isobutyryl L-carnitine (IBC) in plasma (Chapter 2). Next, we evaluated the interactions with FDA-approved tyrosine kinase inhibitors (TKIs) with MATE1 transporter, which is highly expressed in the apical membrane of renal tubular cells, and evaluated the effect of MATE1 inhibition on the safety or DDI liability of oxaliplatin-based chemotherapy (Chapter 3). Finally, we characterized the transport mechanism of dofetilide, a class III anti-arrhythmic drug. We investigated the in vitro, ex vivo, and in vivo DDI potential of dofetilide, and the influence of MATE1 transporter on dofetilide disposition. In addition, we developed a physiologically-based pharmacokinetic (PBPK) model to predict transporter-mediated DDIs (Chapter 4).
The Roles Of The Polyspecific Organic Cation Transporters In The Disposition Of Meta Iodobenzylguanidine And Implications For Toxicities And Drug Interactions
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Author : Antonio Jesús López Quiñones
language : en
Publisher:
Release Date : 2021
The Roles Of The Polyspecific Organic Cation Transporters In The Disposition Of Meta Iodobenzylguanidine And Implications For Toxicities And Drug Interactions written by Antonio Jesús López Quiñones and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2021 with categories.
meta-Iodobenzylguanidine (mIBG) is a radiopharmaceutical used as diagnostic agent and a targeted radiotherapy for neuroendocrine cancers. 131I-mIBG enters the cancer cells through the human norepinephrine transporter (hNET) where radioactive decay of 131I causes DNA damage, cell death, and tumor necrosis. Despite its selective accumulation in neuroendocrine tumors, mIBG distributes in several normal tissues and leads to tissue-specific radiation toxicities. The overall goal of this dissertation is to understand the mechanisms involved in the pharmacokinetics and tissue distribution of mIBG. The studies were designed to: 1) characterize the uptake kinetics and interactions of the polyspecific organic cation transporters and their role in the disposition of mIBG and 2) elucidate the impact of organic cation transporter 3 (OCT3) on the pharmacokinetics and tissue distribution of mIBG. To characterize the contribution of the human organic cation transporter 1, 2, and 3 (hOCT1, hOCT2, and hOCT3) and the human multidrug toxin and extrusion protein 1 and 2-K (hMATE1 and hMATE2-K), we conducted in vitro uptake and inhibition assays in HEK293 cells transfected with the transporters. We showed that mIBG is efficiently transported by hOCT1-3 and hMATE1/2-K with comparable uptake kinetics to hNET. We further demonstrated that mIBG is transported across a hOCT2h/MATE1 double-transfected MDCK monolayer, suggesting that the hOCT2/hMATE pathway is involved in renal secretion of mIBG. We conducted an inhibition screen of mIBG uptake by anticancer drugs used for neuroblastoma and showed that irinotecan selectively inhibited hOCT1 while crizotinib preferentially inhibited hOCT3. We proposed that the polyspecific organic cation transporters mediate the tissue distribution and elimination of mIBG and these transporters can be targeted to reduce tissue accumulation and toxicity, enhance the tumor-to-tissue uptake ratio, and predict and prevent adverse drug interactions for mIBG. To elucidate the impact of OCT3 on the pharmacokinetics and tissue distribution of mIBG, we conducted an in vivo pharmacokinetic and biodistribution study in a Oct3 knockout mouse model. We first developed and validated a bioanalytical LC-MS/MS method for the quantification of non-radiolabeled mIBG in plasma and tissue samples. We demonstrated that the method was accurate, specific, and was devoid of matrix effects in the different biological matrices. The pharmacokinetic data revealed that intact mIBG accumulates in the thyroid, a site of long-term and severe hypothyroidism in neuroendocrine patients. Deletion of Oct3 did not affect the plasma pharmacokinetics of mIBG. Most importantly, we found that Oct3 is a key facilitator for accumulation of mIBG in the heart. In contrast to the conventional but unproven notion that cardiac mIBG uptake is mediated by the norepinephrine transporter, this study in Oct3 knockout mice unequivocally showed that approximately 83% of mIBG exposure in the heart is mediated by OCT3. OCT3-mediated uptake of mIBG in the heart is likely responsible for the severe cardiotoxicities seen in neuroendocrine cancer patients receiving 131I-mIBG therapy. Besides its use in radiotherapy for neuroendocrine cancers, 123I-mIBG is FDA-approved for cardiac imaging and evaluation of heart failure and ventricular arrhythmias. Thus, our finding that OCT3 is the major determinant for mIBG uptake in the heart has important diagnostic implications for 123I-mIBG imaging of cardiovascular diseases. In addition to the reduced accumulation in the heart, deletion of Oct3 reduced the accumulation of mIBG in the skeletal muscle, salivary glands, and the lung. These data indicate that reducing OCT3 activity can lead to drastic changes to tissue exposure of mIBG and may reduce toxicities of 131I-mIBG therapy. In summary, this dissertation research has greatly contributed to our understanding of the mechanisms involved in the disposition, toxicity, and drug interactions of mIBG. A clinically relevant finding of this research is that OCT3 is a key determinant of tissue accumulation of mIBG in several tissues, especially in the heart. Ultimately, these findings will help introduce clinical strategies in modulating OCT3 activity to improve the diagnosis and therapeutic efficacy of mIBG in neuroendocrine cancers and other diseases.
The Role Of Organic Cation Transporters In The Pharmacokinetics Of Clinically Relevant Dna Damaging Agents
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Author : Arturo Papaluca
language : en
Publisher:
Release Date : 2018
The Role Of Organic Cation Transporters In The Pharmacokinetics Of Clinically Relevant Dna Damaging Agents written by Arturo Papaluca and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018 with categories.
In cellular systems, nutrient homeostasis - defined as the ability of a system to maintain in equilibrium nutrient concentrations within fluctuating gradients relative to the internal and external environment - is essential to thrive in harsh conditions. Between the intracellular and extracellular space of the cell membrane, a plethora of molecular and cellular signalling cues interact to coordinate the maintenance of cellular homeostasis. One of the main mechanisms that controls this interaction is orchestrated by membrane proteins. These membrane proteins exist in several classes, structures and functions and are specialized in controlling the traffic of all sorts of nutrients and molecules across the membrane. The aim of this study was to investigate the structure-function relationship of Organic Cation Transporters (OCTs), one of the most important family of membrane proteins. OCTs are involved in the physiological uptake of various nutrients and recent evidences show that these transporters may be far more important in regulating the entry of xenobiotics and therapeutic drugs into cells. The soil nematode Caenorhabditis elegans has provided powerful insights into the roles of OCTs. This nematode uses the membrane-bound transporter OCT-1 as an uptake transporter, which has been classified as an organic cation transporter based on the transport of the prototypical substrate, the ammonium cation tetraethylammonium (TEA) (Wu et al. 1999). Nearly a decade and a half later, it was shown that OCT-1 transports the antioxidant ergothioneine (Cheah et al., 2013). DNA sequence analysis revealed the existence of additional and related transporters such as OCT-2 in C. elegans; however, the roles of OCT-2 have not been described so far. With this in mind, we set out to investigate whether OCT-1 and OCT-2 might coordinate and share the responsibilities in the uptake of cationic compounds in C. elegans. In this thesis, we unveil for the first time the role of OCT-2 in C. elegans. We showed that, unexpectadly, OCT-1 has little role in the uptake of cationic compounds; nonetheless it exerts regulatory functions on oct-2 expression. In the absence of oct-1, oct-2 expression is significantly upregulated and, thus, it is OCT-2 that serves as the major uptake transporter for clinically relevant chemotherapeutic drugs such as doxorubicin, cisplatin and methotrexate used for several cancer treatments. Our research therefore refutes the initial hypothesis that OCT-1 is/acts as a direct uptake transporter in C. elegans. In this work, we established an in vivo screening method to uncover the uptake efficiency of cationic drugs by OCT-1 and OCT-2 by monitoring DNA damage-induced germ cell apoptosis. We observed that deletion of oct-1 gene and/or RNAi-driven downregulation of oct-1 causes upregulation of oct-2, therefore stimulating the uptake of chemotherapeutic drugs and potential toxic metabolites which cause deleterious effects on the animal. Moreover, worms with defective DNA repair pathways were particularly sensitive to the chemotherapeutic agents when oct-2 was upregulated. Importantly, depletion of oct-2 completely impeded the uptake of these drugs thus preventing their genotoxic effects, and hence leading to drug resistance phenotypes. Additionally, we performed an in silico modeling-based comparative screening of OCT-1 and OCT-2, and showed that this approach selectively discriminated amongst ligands that bind robustly to OCT-2 and not OCT-1. We validated this approach in vivo, and demonstrated that OCT-2-dependent transport of DNA-damaging compounds successfully sensitized worms with defective DNA repair pathways, and this effect was reversed once oct-2 was downregulated. Collectively, these experimental methods serve as a proof of concept in studying key characteristics of relevant cationic transporters. Applying in silico methods for the preselection of target molecules and subsequent validation with our OCTs-based in vivo model will undoubtedly increase the success of chemotherapeutics and screening of newly synthesized molecules with a cost-efficient model system. Our work has pivotal implications, as it indicates that (i) hyperactive uptake transporters are likely to import abnormally high concentrations of genotoxic compounds and metabolites over many years causing genomic instability and eventually cancers and (ii) these uptake transporters may hold the key to the mechanisms of drug resistance observed in many types of cancers. In short, these results underscore the importance of uptake transporters in regulating the entry of chemotherapeutic drugs into cells and raises the possibility that drug-resistance and drug-sensitive responses observed in cancer patients could be governed at the level of drug uptake. This study is therefore pivotal as it exploits uptake transporters as a novel approach to expand on several drug screening programs using C. elegans. Thus, our work has immediate applications to a broad range of disciplines. Finally, in a related theme, we present the discovery of a new DNA repair mechanism whereby lesions created by the nucleoside 5-hydroxymethyuracil (5-hmU) are removed by the base excision repair pathway. In this work, we examined the in vivo roles of four base-excision DNA repair enzymes in C. elegans - the two DNA glycosylases UNG-1 and NTH-1 and the two AP endonucleases APN-1 and EXO-3 - in processing the oxidatively modified product of thymine, 5-hmU. C. elegans UNG-1 has been previously characterized in vitro to remove uracil, while NTH-1 was shown to remove thymine glycol, 5-formyl cytosine and 5-hmU. Likewise, the two AP endonucleases have been characterized and both can incise abasic sites and remove 3'-blocking lesions at DNA single strand breaks. However, APN-1 is distinct from EXO-3, as it possesses two additional activities, a 3'- to 5'-exonulease activity and a nucleotide incision repair activity that acts directly on certain oxidatively modified bases. Herein, we used C. elegans mutants and observe that ung-1 mutants exhibited a decrease in brood size and lifespan, and an elevated level of germ cell apoptosis when challenged with 5-hmU. Similar phenotypes were seen with apn-1 mutant, which were exacerbated by RNAi downregulation of apn-1 in the ung-1 mutant. The nth-1 or exo-3 mutants displayed wild type phenotypes towards 5-hmU. We propose a model suggesting that UNG-1 is involved in removing 5-hmU incorporated into the genome and the resulting abasic site is cleaved by APN-1 or EXO-3. In the absence of UNG-1, the 5-hmU is removed by NTH-1, which creates a genotoxic 3'-blocking lesion that requires the action of the 3'-diesterase or 3'- to 5'-exonuclease activity of APN-1. Our data provide the first evidence that C. elegans UNG-1 possesses the ability to remove 5-hmU in vivo, which may have been replaced with SMUG1-like activity in mammalian cells.