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Wang X, Yang C, Huang C, Wang W. Dysfunction of the carnitine cycle in tumor progression. Heliyon 2024; 10:e35961. [PMID: 39211923 PMCID: PMC11357771 DOI: 10.1016/j.heliyon.2024.e35961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 08/06/2024] [Accepted: 08/06/2024] [Indexed: 09/04/2024] Open
Abstract
The carnitine cycle is responsible for the transport of cytoplasmic fatty acids to the mitochondria for subsequent β-oxidation to maintain intracellular energy homeostasis. Recent studies have identified abnormalities in the carnitine cycle in various types of tumors; these abnormalities include the altered expression levels of carnitine cycle-related metabolic enzymes and transport proteins. Dysfunction of the carnitine cycle has been shown to influence tumorigenesis and progression by altering intracellular oxidative and inflammatory status or regulating tumor metabolic flexibility. Many therapeutic strategies targeting the carnitine cycle are actively being explored to modify the dysfunction of the carnitine cycle in patients with malignant tumors; such approaches include carnitine cycle-related enzyme inhibitors and exogenous carnitine supplementation. Therefore, here, we review the studies of carnitine in tumors, aiming to scientifically illustrate the dysfunction of the carnitine cycle in tumor progression and provide new ideas for further research.
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Affiliation(s)
- Xiangjun Wang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Chuanxin Yang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Chao Huang
- Department of Cell Biology, Medical School, Kunming University of Science and Technology, Kunming, 650500, China
| | - Wei Wang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
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2
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Thomas TA, Francis RO, Zimring JC, Kao JP, Nemkov T, Spitalnik SL. The Role of Ergothioneine in Red Blood Cell Biology: A Review and Perspective. Antioxidants (Basel) 2024; 13:717. [PMID: 38929156 PMCID: PMC11200860 DOI: 10.3390/antiox13060717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 06/03/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024] Open
Abstract
Oxidative stress can damage tissues and cells, and their resilience or susceptibility depends on the robustness of their antioxidant mechanisms. The latter include small molecules, proteins, and enzymes, which are linked together in metabolic pathways. Red blood cells are particularly susceptible to oxidative stress due to their large number of hemoglobin molecules, which can undergo auto-oxidation. This yields reactive oxygen species that participate in Fenton chemistry, ultimately damaging their membranes and cytosolic constituents. Fortunately, red blood cells contain robust antioxidant systems to enable them to circulate and perform their physiological functions, particularly delivering oxygen and removing carbon dioxide. Nonetheless, if red blood cells have insufficient antioxidant reserves (e.g., due to genetics, diet, disease, or toxin exposure), this can induce hemolysis in vivo or enhance susceptibility to a "storage lesion" in vitro, when blood donations are refrigerator-stored for transfusion purposes. Ergothioneine, a small molecule not synthesized by mammals, is obtained only through the diet. It is absorbed from the gut and enters cells using a highly specific transporter (i.e., SLC22A4). Certain cells and tissues, particularly red blood cells, contain high ergothioneine levels. Although no deficiency-related disease has been identified, evidence suggests ergothioneine may be a beneficial "nutraceutical." Given the requirements of red blood cells to resist oxidative stress and their high ergothioneine content, this review discusses ergothioneine's potential importance in protecting these cells and identifies knowledge gaps regarding its relevance in enhancing red blood cell circulatory, storage, and transfusion quality.
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Affiliation(s)
- Tiffany A. Thomas
- Laboratory of Transfusion Biology, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; (T.A.T.)
| | - Richard O. Francis
- Laboratory of Transfusion Biology, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; (T.A.T.)
| | - James C. Zimring
- Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
| | - Joseph P. Kao
- Center for Biomedical Engineering, Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Travis Nemkov
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Denver, CO 80203, USA
| | - Steven L. Spitalnik
- Laboratory of Transfusion Biology, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; (T.A.T.)
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3
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Tamas C, Tamas F, Kovecsi A, Cehan A, Balasa A. Metabolic Contrasts: Fatty Acid Oxidation and Ketone Bodies in Healthy Brains vs. Glioblastoma Multiforme. Int J Mol Sci 2024; 25:5482. [PMID: 38791520 PMCID: PMC11122426 DOI: 10.3390/ijms25105482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/09/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
The metabolism of glucose and lipids plays a crucial role in the normal homeostasis of the body. Although glucose is the main energy substrate, in its absence, lipid metabolism becomes the primary source of energy. The main means of fatty acid oxidation (FAO) takes place in the mitochondrial matrix through β-oxidation. Glioblastoma (GBM) is the most common form of primary malignant brain tumor (45.6%), with an incidence of 3.1 per 100,000. The metabolic changes found in GBM cells and in the surrounding microenvironment are associated with proliferation, migration, and resistance to treatment. Tumor cells show a remodeling of metabolism with the use of glycolysis at the expense of oxidative phosphorylation (OXPHOS), known as the Warburg effect. Specialized fatty acids (FAs) transporters such as FAT, FABP, or FATP from the tumor microenvironment are overexpressed in GBM and contribute to the absorption and storage of an increased amount of lipids that will provide sufficient energy used for tumor growth and invasion. This review provides an overview of the key enzymes, transporters, and main regulatory pathways of FAs and ketone bodies (KBs) in normal versus GBM cells, highlighting the need to develop new therapeutic strategies to improve treatment efficacy in patients with GBM.
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Affiliation(s)
- Corina Tamas
- Doctoral School of Medicine and Pharmacy, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania;
- Department of Neurosurgery, Emergency Clinical County Hospital, 540136 Targu Mures, Romania;
- Department of Neurosurgery, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania
| | - Flaviu Tamas
- Doctoral School of Medicine and Pharmacy, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania;
- Department of Neurosurgery, Emergency Clinical County Hospital, 540136 Targu Mures, Romania;
- Department of Neurosurgery, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania
| | - Attila Kovecsi
- Department of Morphopathology, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania;
- Department of Morphopathology, Emergency Clinical County Hospital, 540136 Targu Mures, Romania
| | - Alina Cehan
- Department of Plastic, Esthetics and Reconstructive Surgery, Emergency Clinical County Hospital, 540136 Targu Mures, Romania;
| | - Adrian Balasa
- Department of Neurosurgery, Emergency Clinical County Hospital, 540136 Targu Mures, Romania;
- Department of Neurosurgery, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania
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Low Plasma Ergothioneine Predicts Cognitive and Functional Decline in an Elderly Cohort Attending Memory Clinics. Antioxidants (Basel) 2022; 11:antiox11091717. [PMID: 36139790 PMCID: PMC9495818 DOI: 10.3390/antiox11091717] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 12/20/2022] Open
Abstract
Low blood concentrations of the diet-derived compound ergothioneine (ET) have been associated with cognitive impairment and cerebrovascular disease (CeVD) in cross-sectional studies, but it is unclear whether ET levels can predict subsequent cognitive and functional decline. Here, we examined the temporal relationships between plasma ET status and cognition in a cohort of 470 elderly subjects attending memory clinics in Singapore. All participants underwent baseline plasma ET measurements as well as neuroimaging for CeVD and brain atrophy. Neuropsychological tests of cognition and function were assessed at baseline and follow-up visits for up to five years. Lower plasma ET levels were associated with poorer baseline cognitive performance and faster rates of decline in function as well as in multiple cognitive domains including memory, executive function, attention, visuomotor speed, and language. In subgroup analyses, the longitudinal associations were found only in non-demented individuals. Mediation analyses showed that the effects of ET on cognition seemed to be largely explainable by severity of concomitant CeVD, specifically white matter hyperintensities, and brain atrophy. Our findings support further assessment of plasma ET as a prognostic biomarker for accelerated cognitive and functional decline in pre-dementia and suggest possible therapeutic and preventative measures.
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Antioxidant and Neuroprotective Effects of Paeonol against Oxidative Stress and Altered Carrier-Mediated Transport System on NSC-34 Cell Lines. Antioxidants (Basel) 2022; 11:antiox11071392. [PMID: 35883881 PMCID: PMC9311606 DOI: 10.3390/antiox11071392] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/11/2022] [Accepted: 07/14/2022] [Indexed: 02/05/2023] Open
Abstract
Paeonol is a naturally occurring phenolic agent that attenuates neurotoxicity in neurodegenerative diseases. We aimed to investigate the antioxidant and protective effects of paeonol and determine its transport mechanism in wild-type (WT; NSC-34/hSOD1WT) and mutant-type (MT; NSC-34/hSOD1G93A) motor neuron-like amyotrophic lateral sclerosis (ALS) cell lines. Cytotoxicity induced by glutamate, lipopolysaccharides, and H2O2 reduced viability of cell; however, the addition of paeonol improved cell viability against neurotoxicity. The [3H]paeonol uptake was increased in the presence of H2O2 in both cell lines. Paeonol recovered ALS model cell lines by reducing mitochondrial oxidative stress induced by glutamate. The transport of paeonol was time-, concentration-, and pH-dependent in both NSC-34 cell lines. Kinetic parameters showed two transport sites with altered affinity and capacity in the MT cell line compared to the WT cell line. [3H]Paeonol uptake increased in the MT cell line transfected with organic anion transporter1 (Oat1)/Slc22a6 small interfering RNA compared to that in the control. Plasma membrane monoamine transporter (Pmat) was also involved in the uptake of paeonol by ALS model cell lines. Overall, paeonol exhibits neuroprotective activity via a carrier-mediated transport system and may be a beneficial therapy for preventing motor neuronal damage under ALS-like conditions.
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Abstract
Significance: Ergothioneine (ET) is an unusual sulfur-containing amino acid derived from histidine, acquired predominantly from food. Its depletion is associated with deleterious consequences in response to stress stimuli in cell culture models, prompting us to classify it as a vitamin in 2010, which was later supported by in vivo studies. ET is obtained from a variety of foods and is taken up by a selective transporter. ET possesses antioxidant and anti-inflammatory properties that confer cytoprotection. ET crosses the blood-brain barrier and has been reported to have beneficial effects in the brain. In this study, we discuss the cytoprotective and neuroprotective properties of ET, which may be harnessed for combating neurodegeneration and decline during aging. Recent Advances: The designation of ET as a stress vitamin is gaining momentum, opening a new field of investigation involving small molecules that are essential for optimal physiological functioning and maintenance of health span. Critical Issues: Although ET was discovered more than a century ago, its physiological functions are still being elucidated, especially in the brain. As ET is present in most foods, toxicity associated with its deprivation has been difficult to assess. Future Directions: Using genetically engineered cells and mice, it may now be possible to elucidate roles of ET. This coupled with advances in genomics and metabolomics may lead to identification of ET function. As ET is a stable antioxidant with anti-inflammatory properties, whose levels decline during aging, supplementing ET in the diet or consuming an ET-rich diet may prove beneficial. Antioxid. Redox Signal. 36, 1306-1317.
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Affiliation(s)
- Bindu D Paul
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of The Solomon H. Snyder Department of Neuroscience, and Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Akanuma SI, Han M, Murayama Y, Kubo Y, Hosoya KI. Differences in Cerebral Distribution between Imipramine and Paroxetine via Membrane Transporters at the Rat Blood-Brain Barrier. Pharm Res 2022; 39:223-237. [PMID: 35112227 DOI: 10.1007/s11095-022-03179-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 01/24/2022] [Indexed: 12/14/2022]
Abstract
PURPOSE The present study aimed to elucidate the transport properties of imipramine and paroxetine, which are the antidepressants, across the blood-brain barrier (BBB) in rats. METHODS In vivo influx and efflux transport of imipramine and paroxetine across the BBB were tested using integration plot analysis and a combination of brain efflux index and brain slice uptake studies, respectively. Conditionally immortalized rat brain capillary endothelial cells, TR-BBB13 cells, were utilized to characterize imipramine and paroxetine transport at the BBB in vitro. RESULTS The in vivo influx clearance of [3H]imipramine and [3H]paroxetine in rats was determined to be 0.322 mL/(min·g brain) and 0.313 mL/(min·g brain), respectively. The efflux clearance of [3H]imipramine and [3H]paroxetine was 0.380 mL/(min·g brain) and 0.126 mL/(min·g brain), respectively. These results suggest that the net flux of paroxetine, but not imipramine, at the BBB in vivo was dominated by transport to the brain from the circulating blood. The uptake of imipramine and paroxetine by TR-BBB13 cells exhibited time- and temperature-dependence and one-saturable kinetics with a Km of 37.6 μM and 89.2 μM, respectively. In vitro uptake analyses of extracellular ion dependency and the effect of substrates/inhibitors for organic cation transporters and transport systems revealed minor contributions to known transporters and transport systems and the difference in transport properties in the BBB between imipramine and paroxetine. CONCLUSIONS Our study showed the comprehensive outcomes of imipramine and paroxetine transport at the BBB, implying that molecular mechanism(s) distinct from previously reported transporters and transport systems are involved in the transport.
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Affiliation(s)
- Shin-Ichi Akanuma
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
| | - Myeongrae Han
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Yuka Murayama
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Yoshiyuki Kubo
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Ken-Ichi Hosoya
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
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Magdy T, Jouni M, Kuo H, Weddle CJ, Lyra–Leite D, Fonoudi H, Romero–Tejeda M, Gharib M, Javed H, Fajardo G, Ross CJD, Carleton BC, Bernstein D, Burridge PW. Identification of Drug Transporter Genomic Variants and Inhibitors That Protect Against Doxorubicin-Induced Cardiotoxicity. Circulation 2022; 145:279-294. [PMID: 34874743 PMCID: PMC8792344 DOI: 10.1161/circulationaha.121.055801] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND Multiple pharmacogenomic studies have identified the synonymous genomic variant rs7853758 (G > A, L461L) and the intronic variant rs885004 in SLC28A3 (solute carrier family 28 member 3) as statistically associated with a lower incidence of anthracycline-induced cardiotoxicity. However, the true causal variant(s), the cardioprotective mechanism of this locus, the role of SLC28A3 and other solute carrier (SLC) transporters in anthracycline-induced cardiotoxicity, and the suitability of SLC transporters as targets for cardioprotective drugs has not been investigated. METHODS Six well-phenotyped, doxorubicin-treated pediatric patients from the original association study cohort were recruited again, and human induced pluripotent stem cell-derived cardiomyocytes were generated. Patient-specific doxorubicin-induced cardiotoxicity (DIC) was then characterized using assays of cell viability, activated caspase 3/7, and doxorubicin uptake. The role of SLC28A3 in DIC was then queried using overexpression and knockout of SLC28A3 in isogenic human-induced pluripotent stem cell-derived cardiomyocytes using a CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9). Fine-mapping of the SLC28A3 locus was then completed after SLC28A3 resequencing and an extended in silico haplotype and functional analysis. Genome editing of the potential causal variant was done using cytosine base editor. SLC28A3-AS1 overexpression was done using a lentiviral plasmid-based transduction and was validated using stranded RNA-sequencing after ribosomal RNA depletion. Drug screening was done using the Prestwick Chemical Library (n = 1200), followed by in vivo validation in mice. The effect of desipramine on doxorubicin cytotoxicity was also investigated in 8 cancer cell lines. RESULTS Here, using the most commonly used anthracycline, doxorubicin, we demonstrate that patient-derived cardiomyocytes recapitulate the cardioprotective effect of the SLC28A3 locus and that SLC28A3 expression influences the severity of DIC. Using Nanopore-based fine-mapping and base editing, we identify a novel cardioprotective single nucleotide polymorphism, rs11140490, in the SLC28A3 locus; its effect is exerted via regulation of an antisense long noncoding RNA (SLC28A3-AS1) that overlaps with SLC28A3. Using high-throughput drug screening in patient-derived cardiomyocytes and whole organism validation in mice, we identify the SLC competitive inhibitor desipramine as protective against DIC. CONCLUSIONS This work demonstrates the power of the human induced pluripotent stem cell model to take a single nucleotide polymorphism from a statistical association through to drug discovery, providing human cell-tested data for clinical trials to attenuate DIC.
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Affiliation(s)
- Tarek Magdy
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL.,Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Mariam Jouni
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL.,Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Hui–Hsuan Kuo
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL.,Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Carly J. Weddle
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL.,Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Davi Lyra–Leite
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL.,Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Hananeh Fonoudi
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL.,Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Marisol Romero–Tejeda
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL.,Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Mennat Gharib
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL.,Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Hoor Javed
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL.,Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Giovanni Fajardo
- Department of Pediatrics (Division of Cardiology), Stanford University School of Medicine, Stanford, CA
| | - Colin J. D. Ross
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada.,Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Bruce C. Carleton
- British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada.,Division of Translational Therapeutics Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.,Pharmaceutical Outcomes Programme, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada
| | - Daniel Bernstein
- Department of Pediatrics (Division of Cardiology), Stanford University School of Medicine, Stanford, CA
| | - Paul W. Burridge
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL.,Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL
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Biological Distribution of Orally Administered [ 123I]MIBG for Estimating Gastrointestinal Tract Absorption. Pharmaceutics 2021; 14:pharmaceutics14010061. [PMID: 35056957 PMCID: PMC8779057 DOI: 10.3390/pharmaceutics14010061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/21/2021] [Accepted: 12/24/2021] [Indexed: 11/18/2022] Open
Abstract
Gastrointestinal tract absorption of cationic anticancer drugs and medicines was estimated using whole-body imaging following oral [123I]MIBG administration. [123I]MIBG was added to cultures of human embryonic kidney (HEK)293 cells expressing human organic anion transporting polypeptide (OATP)2B1, carnitine/organic cation transporter (OCTN)1 and OCTN2, and organic cation transporter (OCT)1, OCT2, and OCT3 with and without cimetidine (an OCTN and OCT inhibitor) and L-carnitine (an OCTN inhibitor). Biodistribution analyses and single-photon emission computed tomography (SPECT) imaging in normal and dextran sodium sulfate (DSS)-induced experimental colitis mice were conducted using [123I]MIBG with and without cimetidine. [123I]MIBG uptake was significantly higher in HEK293/OCTN1, 2, and OCT1-3 cells than in mock cells. Uptake via OCTN was inhibited by L-carnitine, whereas OCT-mediated uptake was inhibited by cimetidine. Biodistribution analyses and SPECT imaging studies showed significantly lower accumulation of [123I]MIBG in the blood, heart, liver, and bladder in DSS-induced experimental colitis mice and mice with cimetidine loading compared with normal mice, whereas significantly higher accumulation in the stomach and kidney was observed after [123I]MIBG injection. [123I]MIBG imaging after oral administration can be used to estimate gastrointestinal absorption in the small intestine via OCTN and/or OCT by measuring radioactivity in the heart, liver, and bladder.
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Gründemann D, Hartmann L, Flögel S. The Ergothioneine Transporter (ETT): Substrates and Locations, an Inventory. FEBS Lett 2021; 596:1252-1269. [PMID: 34958679 DOI: 10.1002/1873-3468.14269] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/21/2021] [Accepted: 12/22/2021] [Indexed: 11/07/2022]
Abstract
In all vertebrates including mammals, the ergothioneine transporter ETT (obsolete name OCTN1; human gene symbol SLC22A4) is a powerful and highly specific transporter for the uptake of ergothioneine (ET). ETT is not expressed ubiquitously and only cells with high ETT cell-surface levels can accumulate ET to high concentration. Without ETT, there is no uptake because the plasma membrane is essentially impermeable to this hydrophilic zwitterion. Here, we review the substrate specificity and localization of ETT, which is prominently expressed in neutrophils, monocytes/macrophages, and developing erythrocytes. Most sites of strong expression are conserved across species, but there are also major differences. In particular, we critically analyze the evidence for the expression of ETT in the brain as well as recent data suggesting that the transporter SLC22A15 may transport also ET. We conclude that, to date, ETT remains the only well-defined biomarker for intracellular ET activity. In humans, the ability to take up, distribute, and retain ET depends principally on this transporter.
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Affiliation(s)
- Dirk Gründemann
- Department of Pharmacology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Gleueler Straße 24, 50931, Cologne, Germany
| | - Lea Hartmann
- Department of Pharmacology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Gleueler Straße 24, 50931, Cologne, Germany
| | - Svenja Flögel
- Department of Pharmacology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Gleueler Straße 24, 50931, Cologne, Germany
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Kitsanayanyong L, Ohshima T. Ergothioneine: a potential antioxidative and anti-melanosis agent for food quality preservation. FEBS Lett 2021; 596:1330-1347. [PMID: 34951485 DOI: 10.1002/1873-3468.14267] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 11/09/2022]
Abstract
The global population increase has increased the demand for food products. However, post-harvest deterioration due to oxidation and discoloration results in a drastic loss of food quality and supply. Thus, research has focused on developing strategies to minimize such losses. One of those strategies includes the application of ergothioneine (ET), a potent hydrophilic antioxidant, to several food products so as to overcome their short shelf-life. ET can be synthetic or derived from several species of edible mushrooms and their extracts, which are known sources of natural ET. Given the reported potential of ET in food quality preservation, this review compiles the recent applications of ET as a preservative for maintaining the quality of food commodities.
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Affiliation(s)
- Lalitphan Kitsanayanyong
- Department of Food Science and Technology, Graduate School of Marine Science and Technology, Tokyo University of Marine Science and Technology
| | - Toshiaki Ohshima
- Department of Food Science and Technology, Graduate School of Marine Science and Technology, Tokyo University of Marine Science and Technology
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12
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Comprehensive Evidence of Carrier-Mediated Distribution of Amantadine to the Retina across the Blood-Retinal Barrier in Rats. Pharmaceutics 2021; 13:pharmaceutics13091339. [PMID: 34575415 PMCID: PMC8469395 DOI: 10.3390/pharmaceutics13091339] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/16/2021] [Accepted: 08/24/2021] [Indexed: 11/20/2022] Open
Abstract
Amantadine, a drug used for the blockage of NMDA receptors, is well-known to exhibit neuroprotective effects. Accordingly, assessment of amantadine transport at retinal barriers could result in the application of amantadine for retinal diseases such as glaucoma. The objective of this study was to elucidate the retinal distribution of amantadine across the inner and outer blood–retinal barrier (BRB). In vivo blood-to-retina [3H]amantadine transport was investigated by using the rat retinal uptake index method, which was significantly reduced by unlabeled amantadine. This result indicated the involvement of carrier-mediated processes in the retinal distribution of amantadine. In addition, in vitro model cells of the inner and outer BRB (TR-iBRB2 and RPE-J cells) exhibited saturable kinetics (Km in TR-iBRB2 cells, 79.4 µM; Km in RPE-J cells, 90.5 and 9830 µM). The inhibition of [3H]amantadine uptake by cationic drugs/compounds indicated a minor contribution of transport systems that accept cationic drugs (e.g., verapamil), as well as solute carrier (SLC) organic cation transporters. Collectively, these outcomes suggest that carrier-mediated transport systems, which differ from reported transporters and mechanisms, play a crucial role in the retinal distribution of amantadine across the inner/outer BRB.
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13
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Jala A, Ponneganti S, Vishnubhatla DS, Bhuvanam G, Mekala PR, Varghese B, Radhakrishnanand P, Adela R, Murty US, Borkar RM. Transporter-mediated drug-drug interactions: advancement in models, analytical tools, and regulatory perspective. Drug Metab Rev 2021; 53:285-320. [PMID: 33980079 DOI: 10.1080/03602532.2021.1928687] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 05/05/2021] [Indexed: 02/08/2023]
Abstract
Drug-drug interactions mediated by transporters are a serious clinical concern hence a tremendous amount of work has been done on the characterization of the transporter-mediated proteins in humans and animals. The underlying mechanism for the transporter-mediated drug-drug interaction is the induction or inhibition of the transporter which is involved in the cellular uptake and efflux of drugs. Transporter of the brain, liver, kidney, and intestine are major determinants that alter the absorption, distribution, metabolism, excretion profile of drugs, and considerably influence the pharmacokinetic profile of drugs. As a consequence, transporter proteins may affect the therapeutic activity and safety of drugs. However, mounting evidence suggests that many drugs change the activity and/or expression of the transporter protein. Accordingly, evaluation of drug interaction during the drug development process is an integral part of risk assessment and regulatory requirements. Therefore, this review will highlight the clinical significance of the transporter, their role in disease, possible cause underlying the drug-drug interactions using analytical tools, and update on the regulatory requirement. The recent in-silico approaches which emphasize the advancement in the discovery of drug-drug interactions are also highlighted in this review. Besides, we discuss several endogenous biomarkers that have shown to act as substrates for many transporters, which could be potent determinants to find the drug-drug interactions mediated by transporters. Transporter-mediated drug-drug interactions are taken into consideration in the drug approval process therefore we also provided the extrapolated decision trees from in-vitro to in-vivo, which may trigger the follow-up to clinical studies.
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Affiliation(s)
- Aishwarya Jala
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Srikanth Ponneganti
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Devi Swetha Vishnubhatla
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Gayathri Bhuvanam
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Prithvi Raju Mekala
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Bincy Varghese
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Pullapanthula Radhakrishnanand
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Ramu Adela
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | | | - Roshan M Borkar
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
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14
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Sweet DH. Organic Cation Transporter Expression and Function in the CNS. Handb Exp Pharmacol 2021; 266:41-80. [PMID: 33963461 DOI: 10.1007/164_2021_463] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) represent major control checkpoints protecting the CNS, by exerting selective control over the movement of organic cations and anions into and out of the CNS compartment. In addition, multiple CNS cell types, e.g., astrocytes, ependymal cells, microglia, contribute to processes that maintain the status quo of the CNS milieu. To fulfill their roles, these barriers and cell types express a multitude of transporter proteins from dozens of different transporter families. Fundamental advances over the past few decades in our knowledge of transporter substrates, expression profiles, and consequences of loss of function are beginning to change basic theories regarding the contribution of various cell types and clearance networks to coordinated neuronal signaling, complex organismal behaviors, and overall CNS homeostasis. In particular, transporters belonging to the Solute Carrier (SLC) superfamily are emerging as major contributors, including the SLC22 organic cation/anion/zwitterion family of transporters (includes OCT1-3 and OCTN1-3), the SLC29 facilitative nucleoside family of transporters (includes PMAT), and the SLC47 multidrug and toxin extrusion family of transporters (includes MATE1-2). These transporters are known to interact with neurotransmitters, antidepressant and anxiolytic agents, and drugs of abuse. Clarifying their contributions to the underlying mechanisms regulating CNS permeation and clearance, as well as the health status of astrocyte, microglial and neuronal cell populations, will drive new levels of understanding as to maintenance of the CNS milieu and approaches to new therapeutics and therapeutic strategies in the treatment of CNS disorders. This chapter highlights organic cation transporters belonging to the SLC superfamily known to be expressed in the CNS, providing an overview of their identification, mechanism of action, CNS expression profile, interaction with neurotransmitters and antidepressant/antipsychotic drugs, and results from behavioral studies conducted in loss of function models (knockout/knockdown).
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Affiliation(s)
- Douglas H Sweet
- Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA.
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15
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Cheah IK, Halliwell B. Ergothioneine, recent developments. Redox Biol 2021; 42:101868. [PMID: 33558182 PMCID: PMC8113028 DOI: 10.1016/j.redox.2021.101868] [Citation(s) in RCA: 104] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/14/2021] [Accepted: 01/14/2021] [Indexed: 02/06/2023] Open
Abstract
There has been a recent surge of interest in the unique low molecular weight dietary thiol/thione, ergothioneine. This compound can accumulate at high levels in the body from diet and may play important physiological roles in human health and development, and possibly in prevention and treatment of disease. Blood levels of ergothioneine decline with age and onset of various diseases. Here we highlight recent advances in our knowledge of ergothioneine.
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Affiliation(s)
- Irwin K Cheah
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117596, Singapore; Life Science Institute, Neurobiology Programme, Centre for Life Sciences, National University of Singapore, 117456, Singapore
| | - Barry Halliwell
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117596, Singapore; Life Science Institute, Neurobiology Programme, Centre for Life Sciences, National University of Singapore, 117456, Singapore.
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16
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Kurosawa K, Chiba K, Noguchi S, Nishimura T, Tomi M. Development of a Pharmacokinetic Model of Transplacental Transfer of Metformin to Predict In Vivo Fetal Exposure. Drug Metab Dispos 2020; 48:1293-1302. [PMID: 33051249 DOI: 10.1124/dmd.120.000127] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 09/14/2020] [Indexed: 11/22/2022] Open
Abstract
Two types of systems are used in ex vivo human placental perfusion studies to predict fetal drug exposures, that is, closed systems with recirculation of the maternal and fetal buffer and open systems using a single-pass mode without recirculation. The in vivo fetal/maternal (F:M) ratio of metformin, a cationic drug that crosses the placenta, is consistent with that reported in an open system ex vivo but not with that in a closed system. In the present study, we aimed to develop a pharmacokinetic (PK) model of transplacental transfer of metformin to predict in vivo fetal exposure to metformin and to resolve the apparent inconsistency between open and closed ex vivo systems. The developed model shows that the difference between open and closed systems is due to the difference in the time required to achieve the steady state. The model-predicted F:M ratio (approx. 0.88) is consistent with reported in vivo values [mean (95% confidence interval): 1.10 (0.69-1.51)]. The model incorporates bidirectional transport via organic cation transporter 3 (OCT3) at the basal plasma membrane, and simulations indicate that the use of trimethoprim (an OCT3 inhibitor) to prevent microbial growth in the placenta ex vivo has a negligible effect on the overall maternal-to-fetal and fetal-to-maternal clearances. The model could successfully predict in vivo fetal exposure using ex vivo human placental perfusion data from both closed and open systems. This transplacental PK modeling approach is expected to be useful for evaluating human fetal exposures to other poorly permeable compounds, besides metformin. SIGNIFICANCE STATEMENT: We developed a pharmacokinetic model of transplacental transfer of metformin, used to treat gestational diabetes mellitus, in order to predict in vivo fetal exposure and resolve the discrepancy between reported findings in open and closed ex vivo perfusion systems. The discrepancy is due to a difference in the time required to reach the steady state. The model can predict in vivo fetal exposure using data from both closed and open systems.
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Affiliation(s)
- Ken Kurosawa
- Department of Clinical Pharmacology, Janssen Pharmaceutical K.K., Tokyo, Japan (K.K.); Laboratory of Clinical Pharmacology, Yokohama University of Pharmacy, Kanagawa, Japan (K.C.); and Faculty of Pharmacy, Keio University of Pharmacy, Tokyo, Japan (K.K., S.N., T.N., M.T.)
| | - Koji Chiba
- Department of Clinical Pharmacology, Janssen Pharmaceutical K.K., Tokyo, Japan (K.K.); Laboratory of Clinical Pharmacology, Yokohama University of Pharmacy, Kanagawa, Japan (K.C.); and Faculty of Pharmacy, Keio University of Pharmacy, Tokyo, Japan (K.K., S.N., T.N., M.T.)
| | - Saki Noguchi
- Department of Clinical Pharmacology, Janssen Pharmaceutical K.K., Tokyo, Japan (K.K.); Laboratory of Clinical Pharmacology, Yokohama University of Pharmacy, Kanagawa, Japan (K.C.); and Faculty of Pharmacy, Keio University of Pharmacy, Tokyo, Japan (K.K., S.N., T.N., M.T.)
| | - Tomohiro Nishimura
- Department of Clinical Pharmacology, Janssen Pharmaceutical K.K., Tokyo, Japan (K.K.); Laboratory of Clinical Pharmacology, Yokohama University of Pharmacy, Kanagawa, Japan (K.C.); and Faculty of Pharmacy, Keio University of Pharmacy, Tokyo, Japan (K.K., S.N., T.N., M.T.)
| | - Masatoshi Tomi
- Department of Clinical Pharmacology, Janssen Pharmaceutical K.K., Tokyo, Japan (K.K.); Laboratory of Clinical Pharmacology, Yokohama University of Pharmacy, Kanagawa, Japan (K.C.); and Faculty of Pharmacy, Keio University of Pharmacy, Tokyo, Japan (K.K., S.N., T.N., M.T.)
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17
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Juraszek B, Czarnecka-Herok J, Nałęcz KA. Glioma cells survival depends both on fatty acid oxidation and on functional carnitine transport by SLC22A5. J Neurochem 2020; 156:642-657. [PMID: 32654140 DOI: 10.1111/jnc.15124] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/03/2020] [Accepted: 07/07/2020] [Indexed: 02/06/2023]
Abstract
Gliomas are the most common primary malignant brain tumor in adults, but current treatment for glioblastoma multiforme (GBM) is insufficient. Even though glucose is the primary energetic substrate of glioma cells, they are capable of using fatty acids to generate energy. Fatty acid oxidation (FAO) in mitochondria requires L-carnitine for the formation of acylcarnitines by carnitine palmitoylotransferase 1 (CPT1) and further transport of acyl carnitine esters to mitochondrial matrix. Carnitine can be delivered to the cell by an organic cation/carnitine transporter-SLC22A5/OCTN2. In this study, we show that SLC22A5 is up-regulated in glioma cells and that they vary in the amount of SLC22A5 in the plasma membrane. Research on glioma cells (lines U87MG, LN229, T98G) with various expression levels of SLC22A5 demonstrated a correlation between the FAO rate, the level of the transporter, and the carnitine transport. Inhibition of carnitine transport by chemotherapeutics, such as vinorelbine and vincristine, led to inhibition of FAO, which was further intensified by etomoxir-a CPT1 inhibitor. This led to reduced viability and increased apoptosis in glioma cells. Modulation of SLC22A5 level by either silencing or up-regulation of SLC22A5 also affected glioma cell survival in a FAO-dependent way. These observations suggest that the survival of glioma cells is heavily reliant on both FAO and SLC22A5 activity, as well as that CPT1 and SLC22A5 might be possible drug targets.
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Affiliation(s)
- Barbara Juraszek
- Laboratory of Transport through Biomembranes, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Joanna Czarnecka-Herok
- Laboratory of Molecular Bases of Ageing, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Katarzyna A Nałęcz
- Laboratory of Transport through Biomembranes, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
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18
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Tupova L, Hirschmugl B, Sucha S, Pilarova V, Székely V, Bakos É, Novakova L, Özvegy-Laczka C, Wadsack C, Ceckova M. Interplay of drug transporters P-glycoprotein (MDR1), MRP1, OATP1A2 and OATP1B3 in passage of maraviroc across human placenta. Biomed Pharmacother 2020; 129:110506. [PMID: 32768979 DOI: 10.1016/j.biopha.2020.110506] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 06/27/2020] [Accepted: 07/02/2020] [Indexed: 12/16/2022] Open
Abstract
Special attention is required when pharmacological treatment is indicated for a pregnant woman. P-glycoprotein (MDR1) is a well-known transporter localized in the maternal blood-facing apical membrane of placental syncytiotrophoblast and is considered to play an important role in protecting the developing fetus. Maraviroc, a MDR1 substrate that is registered for treatment of HIV infection, shows a low toxicity profile, suggesting favorable tolerability also if administered to pregnant women. Nevertheless, there is only poor understanding to date regarding the extent to which it permeates across the placental barrier and what are the transport mechanisms involved. Endeavoring to clarify the passage of maraviroc across placenta, we used in this study the method of closed-circuit perfusion of maraviroc across human placental cotyledon. The data obtained confirmed slight involvement of MDR1, but they also suggest possible interaction with other transport system(s) working in the opposite direction from that of MDR1. Complementary in vitro studies, including cellular experiments on choriocarcinoma BeWo cells as well as transporter-overexpressing MDCKII and A431 cell lines and accumulation in placental fresh villous fragments, revealed maraviroc transport by MRP1, OATP1A2, and OATP1B3 transporters. Based on mRNA expression data in the placental tissue, isolated trophoblasts, and fetal endothelial cells, especially MRP1 and OATP1A2 seem to play a crucial role in cooperatively driving maraviroc into placental tissue. By the example of maraviroc, we show here the important interplay of transporters in placental drug handling and its possibility to overcome the MDR1-mediated efflux.
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Affiliation(s)
- Lenka Tupova
- Charles University, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Akademika Heyrovskeho 1203, Hradec Kralove, Czech Republic
| | - Birgit Hirschmugl
- Medical University of Graz, Department of Obstetrics and Gynecology, 8036, Graz, Austria
| | - Simona Sucha
- Charles University, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Akademika Heyrovskeho 1203, Hradec Kralove, Czech Republic
| | - Veronika Pilarova
- Charles University, Faculty of Pharmacy in Hradec Kralove, Department of Analytical Chemistry, Akademika Heyrovskeho 1203, Hradec Kralove, Czech Republic
| | - Virág Székely
- Membrane Protein Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Magyar tudósok krt. 2., H-1117, Budapest, Hungary
| | - Éva Bakos
- Membrane Protein Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Magyar tudósok krt. 2., H-1117, Budapest, Hungary
| | - Lucie Novakova
- Charles University, Faculty of Pharmacy in Hradec Kralove, Department of Analytical Chemistry, Akademika Heyrovskeho 1203, Hradec Kralove, Czech Republic
| | - Csilla Özvegy-Laczka
- Membrane Protein Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Magyar tudósok krt. 2., H-1117, Budapest, Hungary
| | - Christian Wadsack
- Medical University of Graz, Department of Obstetrics and Gynecology, 8036, Graz, Austria
| | - Martina Ceckova
- Charles University, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Akademika Heyrovskeho 1203, Hradec Kralove, Czech Republic.
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19
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Jinno N, Furugen A, Kurosawa Y, Kanno Y, Narumi K, Kobayashi M, Iseki K. Effects of single and repetitive valproic acid administration on the gene expression of placental transporters in pregnant rats: An analysis by gestational period. Reprod Toxicol 2020; 96:47-56. [PMID: 32437819 DOI: 10.1016/j.reprotox.2020.04.077] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 04/10/2020] [Accepted: 04/28/2020] [Indexed: 12/17/2022]
Abstract
The use of valproic acid (VPA), an antiepileptic drug, during pregnancy, is known to increase various fetal risks. Since VPA has been known to inhibit histone deacetylases (HDACs); its administration could alter gene transcription levels. However, in vivo effects of VPA administration on placental transporters have not been fully elucidated. The purpose of the present study was to comprehensively evaluate the effects of single and repetitive VPA administration on the expression of placental transporters and analyze them by gestational day. We investigated 18 transporters (8 ATP-binding cassette (ABC) and 10 solute carrier (SLC) transporters) in the placentas of pregnant rats that were orally administered 400 mg/kg/day VPA for one or four days, during mid- or late gestation. In the control rats, 4 ABC transporter genes (Abcb1a, 1b, Abcc2, Abcc4) were upregulated, 3 (Abcc3, Abcc5, Abcg2) downregulated through gestation, whereas 1 (Abcc1) was not changed. Regarding SLC transporters, 6 genes (Slc7a5, Slc16a3, Slc22a3, Slc22a4, Slco2b1, Slco4a1) were increased, 1 (Slc29a1) decreased through gestation, whereas 3 (Slc7a8, Slc22a5, Slco2a1) showed no significant change. Single VPA administration altered the expression of 9 transporters and repetitive administration, 13 transporters. In particular, VPA remarkably decreased Abcc4 and Slc22a4 in late gestation and increased Abcc5 during mid-gestation. Our findings indicated that VPA administration changed transporter expression levels in rat placenta, and suggested that sensitivity to VPA differs across gestational stages.
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Affiliation(s)
- Naoko Jinno
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan
| | - Ayako Furugen
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan
| | - Yuko Kurosawa
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan
| | - Yuki Kanno
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan
| | - Katsuya Narumi
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan
| | - Masaki Kobayashi
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
| | - Ken Iseki
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan
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20
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Anderson JT, Huang KM, Lustberg MB, Sparreboom A, Hu S. Solute Carrier Transportome in Chemotherapy-Induced Adverse Drug Reactions. Rev Physiol Biochem Pharmacol 2020; 183:177-215. [PMID: 32761456 DOI: 10.1007/112_2020_30] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Members of the solute carrier (SLC) family of transporters are responsible for the cellular influx of a broad range of endogenous compounds and xenobiotics. These proteins are highly expressed in the gastrointestinal tract and eliminating organs such as the liver and kidney, and are considered to be of particular importance in governing drug absorption and elimination. Many of the same transporters are also expressed in a wide variety of organs targeted by clinically important anticancer drugs, directly affect cellular sensitivity to these agents, and indirectly influence treatment-related side effects. Furthermore, targeted intervention strategies involving the use of transport inhibitors have been recently developed, and have provided promising lead candidates for combinatorial therapies associated with decreased toxicity. Gaining a better understanding of the complex interplay between transporter-mediated on-target and off-target drug disposition will help guide the further development of these novel treatment strategies to prevent drug accumulation in toxicity-associated organs, and improve the safety of currently available treatment modalities. In this report, we provide an update on this rapidly emerging field with particular emphasis on anticancer drugs belonging to the classes of taxanes, platinum derivatives, nucleoside analogs, and anthracyclines.
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Affiliation(s)
- Jason T Anderson
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Kevin M Huang
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Maryam B Lustberg
- Department of Medical Oncology, The Ohio State University, Comprehensive Cancer Center, Columbus, OH, USA
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Shuiying Hu
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
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21
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Juraszek B, Nałęcz KA. SLC22A5 (OCTN2) Carnitine Transporter-Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer. Molecules 2019; 25:molecules25010014. [PMID: 31861504 PMCID: PMC6982704 DOI: 10.3390/molecules25010014] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 12/12/2019] [Accepted: 12/14/2019] [Indexed: 12/26/2022] Open
Abstract
Oxidation of fatty acids uses l-carnitine to transport acyl moieties to mitochondria in a so-called carnitine shuttle. The process of β-oxidation also takes place in cancer cells. The majority of carnitine comes from the diet and is transported to the cell by ubiquitously expressed organic cation transporter novel family member 2 (OCTN2)/solute carrier family 22 member 5 (SLC22A5). The expression of SLC22A5 is regulated by transcription factors peroxisome proliferator-activated receptors (PPARs) and estrogen receptor. Transporter delivery to the cell surface, as well as transport activity are controlled by OCTN2 interaction with other proteins, such as PDZ-domain containing proteins, protein phosphatase PP2A, caveolin-1, protein kinase C. SLC22A5 expression is altered in many types of cancer, giving an advantage to some of them by supplying carnitine for β-oxidation, thus providing an alternative to glucose source of energy for growth and proliferation. On the other hand, SLC22A5 can also transport several chemotherapeutics used in clinics, leading to cancer cell death.
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22
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Zeng Q, Bai M, Li C, Lu S, Ma Z, Zhao Y, Zhou H, Jiang H, Sun D, Zheng C. Multiple Drug Transporters Contribute to the Placental Transfer of Emtricitabine. Antimicrob Agents Chemother 2019; 63:e00199-19. [PMID: 31160284 PMCID: PMC6658773 DOI: 10.1128/aac.00199-19] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 04/25/2019] [Indexed: 11/20/2022] Open
Abstract
Emtricitabine (FTC) is a first-line antiviral drug recommended for the treatment of AIDS during pregnancy. We hypothesized that transporters located in the placenta contribute to FTC transfer across the blood-placenta barrier. BeWo cells, cell models with stable or transient expression of transporter genes, primary human trophoblast cells (PHTCs), and small interfering RNAs (siRNAs) were applied to demonstrate which transporters were involved. FTC accumulation in BeWo cells was reduced markedly by inhibitors of equilibrative nucleoside transporters (ENTs), concentrative nucleoside transporters (CNTs), organic cation transporters (OCTs), and organic cation/carnitine transporter 1 (OCTN1) and increased by inhibitors of breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs). ENT1, CNT1, OCTN1, MRP1/2/3, and BCRP, but not ENT2, CNT3, OCTN2, or multidrug resistance protein 1 (MDR1), were found to transport FTC. FTC accumulation in PHTCs was decreased significantly by inhibitors of ENTs and OCTN1. These results suggest that ENT1, CNT1, and OCTN1 probably contribute to FTC uptake from maternal circulation to trophoblasts and that ENT1, CNT1, and MRP1 are likely involved in FTC transport between trophoblasts and fetal blood, whereas BCRP and MRP1/2/3 facilitate FTC transport from trophoblasts to maternal circulation. Coexistence of tenofovir or efavirenz with FTC in the cell medium did not influence FTC accumulation in BeWo cells or PHTCs.
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Affiliation(s)
- Qingquan Zeng
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Mengru Bai
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Cui Li
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Shuanghui Lu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zhiyuan Ma
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yunchun Zhao
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hui Zhou
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Huidi Jiang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Dongli Sun
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Caihong Zheng
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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23
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Cheah IK, Ng LT, Ng LF, Lam VY, Gruber J, Huang CYW, Goh FQ, Lim KHC, Halliwell B. Inhibition of amyloid-induced toxicity by ergothioneine in a transgenic Caenorhabditis elegans model. FEBS Lett 2019; 593:2139-2150. [PMID: 31211853 DOI: 10.1002/1873-3468.13497] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 06/13/2019] [Accepted: 06/13/2019] [Indexed: 12/26/2022]
Abstract
The abnormal accumulation of β-amyloid peptide (Aβ) is recognized as a central component in the pathogenesis of Alzheimer disease. While many aspects of Aβ-mediated neurotoxicity remain elusive, Aβ has been associated with numerous underlying pathologies, including oxidative and nitrosative stress, inflammation, metal ion imbalance, mitochondrial dysfunction, and even tau pathology. Ergothioneine (ET), a naturally occurring thiol/thione-derivative of histidine, has demonstrated antioxidant and neuroprotective properties against various oxidative and neurotoxic stressors. This study investigates ET's potential to counteract Aβ-toxicity in transgenic Caenorhabditis elegans overexpressing a human Aβ peptide. The accumulation of Aβ in this model leads to paralysis and premature death. We show that ET dose-dependently reduces Aβ-oligomerization and extends the lifespan and healthspan of the nematodes.
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Affiliation(s)
- Irwin K Cheah
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Life Science Institute, Neurobiology Programme, Centre for Life Sciences, National University of Singapore, Singapore
| | - Li-Theng Ng
- Life Science Institute, Neurobiology Programme, Centre for Life Sciences, National University of Singapore, Singapore
- Yale-NUS College, Singapore
| | | | - Vanessa Y Lam
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Life Science Institute, Neurobiology Programme, Centre for Life Sciences, National University of Singapore, Singapore
| | - Jan Gruber
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Yale-NUS College, Singapore
| | - Cheryl Y W Huang
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Fang-Qin Goh
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Keith H C Lim
- Department of Radiation Oncology, National University Health System, National University Cancer Institute Singapore, Singapore
| | - Barry Halliwell
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Life Science Institute, Neurobiology Programme, Centre for Life Sciences, National University of Singapore, Singapore
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24
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Bai M, Zeng Q, Chen Y, Chen M, Li P, Ma Z, Sun D, Zhou H, Zheng C, Zeng S, Jiang H. Maternal Plasma l-Carnitine Reduction During Pregnancy Is Mainly Attributed to OCTN2-Mediated Placental Uptake and Does Not Result in Maternal Hepatic Fatty Acid β-Oxidation Decline. Drug Metab Dispos 2019; 47:582-591. [PMID: 30918014 DOI: 10.1124/dmd.119.086439] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 03/22/2019] [Indexed: 12/25/2022] Open
Abstract
l-Carnitine (l-Car) plays a crucial role in fatty acid β-oxidation. However, the plasma l-Car concentration in women markedly declines during pregnancy, but the underlying mechanism and its consequences on maternal hepatic β-oxidation have not yet been clarified. Our results showed that the plasma l-Car level in mice at gestation day (GD) 18 was significantly lower than that in nonpregnant mice, and the mean fetal-to-maternal plasma l-Car ratio in GD 18 mice was 3.0. Carnitine/organic cation transporter 2 (OCTN2) was highly expressed in mouse and human placenta and upregulated as gestation proceeds in human placenta, whereas expressions of carnitine transporter (CT) 1, CT2, and amino acid transporter B0,+ were extremely low. Further study revealed that renal peroxisome proliferator-activated receptor α (PPARα) and OCTN2 were downregulated and the renal l-Car level was reduced, whereas the urinary excretion of l-Car was lower in late pregnant mice than in nonpregnant mice. Meanwhile, progesterone (pregnancy-related hormone) downregulated the expression of renal OCTN2 via PPARα-mediated pathway, and inhibited the activity of OCTN2, but estradiol, corticosterone, and cortisol did not. Unexpectedly, the maternal hepatic level of l-Car and β-hydroxybutyrate (an indicator of mitochondrial β-oxidation), and mRNA levels of several enzymes involved in fatty acid β-oxidation in GD 18 mice were higher than that in nonpregnant mice. In conclusion, OCTN2 mediated l-Car transfer across the placenta played a major role in maternal plasma l-Car reduction during pregnancy, which did not subsequently result in maternal hepatic fatty acid β-oxidation decrease.
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Affiliation(s)
- Mengru Bai
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences (M.B., Y.C., M.C., P.L., Z.M., H.Z., S.Z., H.J.) and Women's Hospital, School of Medicine (Q.Z., D.S., C.Z.), Zhejiang University, Hangzhou, People's Republic of China
| | - Qingquan Zeng
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences (M.B., Y.C., M.C., P.L., Z.M., H.Z., S.Z., H.J.) and Women's Hospital, School of Medicine (Q.Z., D.S., C.Z.), Zhejiang University, Hangzhou, People's Republic of China
| | - Yingchun Chen
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences (M.B., Y.C., M.C., P.L., Z.M., H.Z., S.Z., H.J.) and Women's Hospital, School of Medicine (Q.Z., D.S., C.Z.), Zhejiang University, Hangzhou, People's Republic of China
| | - Mingyang Chen
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences (M.B., Y.C., M.C., P.L., Z.M., H.Z., S.Z., H.J.) and Women's Hospital, School of Medicine (Q.Z., D.S., C.Z.), Zhejiang University, Hangzhou, People's Republic of China
| | - Ping Li
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences (M.B., Y.C., M.C., P.L., Z.M., H.Z., S.Z., H.J.) and Women's Hospital, School of Medicine (Q.Z., D.S., C.Z.), Zhejiang University, Hangzhou, People's Republic of China
| | - Zhiyuan Ma
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences (M.B., Y.C., M.C., P.L., Z.M., H.Z., S.Z., H.J.) and Women's Hospital, School of Medicine (Q.Z., D.S., C.Z.), Zhejiang University, Hangzhou, People's Republic of China
| | - Dongli Sun
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences (M.B., Y.C., M.C., P.L., Z.M., H.Z., S.Z., H.J.) and Women's Hospital, School of Medicine (Q.Z., D.S., C.Z.), Zhejiang University, Hangzhou, People's Republic of China
| | - Hui Zhou
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences (M.B., Y.C., M.C., P.L., Z.M., H.Z., S.Z., H.J.) and Women's Hospital, School of Medicine (Q.Z., D.S., C.Z.), Zhejiang University, Hangzhou, People's Republic of China
| | - Caihong Zheng
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences (M.B., Y.C., M.C., P.L., Z.M., H.Z., S.Z., H.J.) and Women's Hospital, School of Medicine (Q.Z., D.S., C.Z.), Zhejiang University, Hangzhou, People's Republic of China
| | - Su Zeng
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences (M.B., Y.C., M.C., P.L., Z.M., H.Z., S.Z., H.J.) and Women's Hospital, School of Medicine (Q.Z., D.S., C.Z.), Zhejiang University, Hangzhou, People's Republic of China
| | - Huidi Jiang
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences (M.B., Y.C., M.C., P.L., Z.M., H.Z., S.Z., H.J.) and Women's Hospital, School of Medicine (Q.Z., D.S., C.Z.), Zhejiang University, Hangzhou, People's Republic of China
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25
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Hausner EA, Elmore SA, Yang X. Overview of the Components of Cardiac Metabolism. Drug Metab Dispos 2019; 47:673-688. [PMID: 30967471 PMCID: PMC7333657 DOI: 10.1124/dmd.119.086611] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 03/26/2019] [Indexed: 12/20/2022] Open
Abstract
Metabolism in organs other than the liver and kidneys may play a significant role in how a specific organ responds to chemicals. The heart has metabolic capability for energy production and homeostasis. This homeostatic machinery can also process xenobiotics. Cardiac metabolism includes the expression of numerous organic anion transporters, organic cation transporters, organic carnitine (zwitterion) transporters, and ATP-binding cassette transporters. Expression and distribution of the transporters within the heart may vary, depending on the patient's age, disease, endocrine status, and various other factors. Several cytochrome P450 (P450) enzyme classes have been identified within the heart. The P450 hydroxylases and epoxygenases within the heart produce hydroxyeicosatetraneoic acids and epoxyeicosatrienoic acids, metabolites of arachidonic acid, which are critical in regulating homeostatic processes of the heart. The susceptibility of the cardiac P450 system to induction and inhibition from exogenous materials is an area of expanding knowledge, as are the metabolic processes of glucuronidation and sulfation in the heart. The susceptibility of various transcription factors and signaling pathways of the heart to disruption by xenobiotics is not fully characterized but is an area with implications for disruption of normal postnatal development, as well as modulation of adult cardiac health. There are knowledge gaps in the timelines of physiologic maturation and deterioration of cardiac metabolism. Cross-species characterization of cardiac-specific metabolism is needed for nonclinical work of optimum translational value to predict possible adverse effects, identify sensitive developmental windows for the design and conduct of informative nonclinical and clinical studies, and explore the possibilities of organ-specific therapeutics.
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Affiliation(s)
- Elizabeth A Hausner
- United States Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, Maryland (E.A.H., X.Y.); and National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (S.A.E.)
| | - Susan A Elmore
- United States Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, Maryland (E.A.H., X.Y.); and National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (S.A.E.)
| | - Xi Yang
- United States Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, Maryland (E.A.H., X.Y.); and National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (S.A.E.)
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Azad MAK, Nation RL, Velkov T, Li J. Mechanisms of Polymyxin-Induced Nephrotoxicity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1145:305-319. [PMID: 31364084 DOI: 10.1007/978-3-030-16373-0_18] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Polymyxin-induced nephrotoxicity is the major dose-limiting factor and can occur in up to 60% of patients after intravenous administration. This chapter reviews the latest literature on the mechanisms of polymyxin-induced nephrotoxicity and its amelioration. After filtration by glomeruli, polymyxins substantially accumulate in renal proximal tubules via receptor-mediated endocytosis mainly by megalin and PEPT2. It is believed that subsequently, a cascade of interconnected events occur, including the activation of death receptor and mitochondrial apoptotic pathways, mitochondrial damage, endoplasmic reticulum stress, oxidative stress and cell cycle arrest. The current literature shows that oxidative stress plays a key role in polymyxin-induced kidney damage. Use of antioxidants have a potential in the attenuation of polymyxin-induced nephrotoxicity, thereby widening the therapeutic window. Mechanistic findings on polymyxin-induced nephrotoxicity are critical for the optimization of their use in the clinic and the discovery of safer polymyxin-like antibiotics.
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Affiliation(s)
- Mohammad A K Azad
- Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Clayton Campus, Melbourne, VIC, Australia
| | - Roger L Nation
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, Melbourne, VIC, Australia
| | - Tony Velkov
- Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia
| | - Jian Li
- Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Clayton Campus, Melbourne, VIC, Australia.
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27
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Tega Y, Yamazaki Y, Akanuma SI, Kubo Y, Hosoya KI. Impact of Nicotine Transport across the Blood-Brain Barrier: Carrier-Mediated Transport of Nicotine and Interaction with Central Nervous System Drugs. Biol Pharm Bull 2018; 41:1330-1336. [PMID: 30175770 DOI: 10.1248/bpb.b18-00134] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Nicotine, an addictive substance, is absorbed from the lungs following inhalation of tobacco smoke, and distributed to various tissues such as liver, brain, and retina. Recent in vivo and in vitro studies suggest the involvement of a carrier-mediated transport process in nicotine transport in the lung, liver, and inner blood-retinal barrier. In addition, in vivo studies of influx and efflux transport of nicotine across the blood-brain barrier (BBB) revealed that blood-to-brain influx transport of nicotine is more dominant than brain-to-blood efflux transport of nicotine. Uptake studies in TR-BBB13 cells, which are an in vitro model cell line of the BBB, suggest the involvement of H+/organic cation antiporter, which is distinct from typical organic cation transporters, in nicotine transport at the BBB. Moreover, inhibition studies in TR-BBB13 cells showed that nicotine uptake was significantly reduced by central nervous system (CNS) drugs, such as antidepressants, anti-Alzheimer's disease drugs, and anti-Parkinson's disease drugs, suggesting that the nicotine transport system can recognize these molecules. The cumulative evidence would be helpful to improve our understanding of smoking-CNS drug interaction for providing appropriate medication.
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Affiliation(s)
- Yuma Tega
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
| | - Yuhei Yamazaki
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
| | - Shin-Ichi Akanuma
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
| | - Yoshiyuki Kubo
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
| | - Ken-Ichi Hosoya
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
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28
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Selective Inhibition on Organic Cation Transporters by Carvedilol Protects Mice from Cisplatin-Induced Nephrotoxicity. Pharm Res 2018; 35:204. [PMID: 30191328 DOI: 10.1007/s11095-018-2486-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 08/24/2018] [Indexed: 10/28/2022]
Abstract
PURPOSE The organic cation transporters (OCTs) and multidrug and toxin extrusions (MATEs), located in the basolateral and apical membrane of proximal tubular cells respectively, are crucial determinants of renal elimination and/or toxicity of cationic drugs such as cisplatin. The purpose of this study was to discover selective OCT inhibitors over MATEs, and explore their potential to protect against cisplatin-induced nephrotoxicity that is clinically common. METHODS The inhibition by select compounds on the uptake of the probe substrate metformin was assessed in HEK293 cells overexpressing human OCT2, OCT1, MATE1, MATE2-K, and mouse Oct2, Oct1, and Mate1. Furthermore, the effects of carvedilol on organic cation transporter-mediated cellular and renal accumulation of metformin and cisplatin, and particularly the toxicity associated with cisplatin, were investigated in HEK293 cells and mice. RESULTS Five selective OCT inhibitors were identified through the screening of forty-one drugs previously reported as the inhibitors of OCTs and/or MATEs. Among them, carvedilol showed the most selectivity on OCTs over MATEs (IC50: 3.6 μM for human OCT2, 103 μM for human MATE1 and 202 μM for human MATE2-K) in the cellular assays in vitro, with the selectivity in mice as well. Moreover, carvedilol treatment could significantly decrease cisplatin accumulation and ameliorate its toxicity both in vitro in cells and in vivo in mouse kidney. CONCLUSIONS Our data indicate that selective inhibition of OCTs by carvedilol may protect from cisplatin-induced nephrotoxicity by restraining the cellular entry of cisplatin via OCTs, while having no impact on its elimination through MATEs.
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29
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Halliwell B, Cheah IK, Tang RMY. Ergothioneine - a diet-derived antioxidant with therapeutic potential. FEBS Lett 2018; 592:3357-3366. [PMID: 29851075 DOI: 10.1002/1873-3468.13123] [Citation(s) in RCA: 184] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 05/22/2018] [Indexed: 12/21/2022]
Abstract
Ergothioneine is a thiol/thione molecule synthesised only by some fungi and bacteria. Nonetheless, it is avidly taken up from the diet by humans and other animals through a transporter, OCTN1, and accumulates to high levels in certain tissues. Ergothioneine is not rapidly metabolised, or excreted in urine and is present in many, if not all, human tissues and body fluids. Ergothioneine has powerful antioxidant and cytoprotective properties in vitro and there is evidence that the body may concentrate it at sites of tissue injury by raising OCTN1 levels. Decreased blood and/or plasma levels of ergothioneine have been observed in some diseases, suggesting that a deficiency could be relevant to the disease onset or progression. This brief Review explores the possible roles of ergothioneine in human health and disease.
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Affiliation(s)
- Barry Halliwell
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore
| | - Irwin K Cheah
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore
| | - Richard M Y Tang
- National University of Singapore Graduate School for Integrative Sciences and Engineering, Singapore, Singapore
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30
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l-Ergothioneine improves the developmental potential of in vitro sheep embryos without influencing OCTN1-mediated cross-membrane transcript expression. ZYGOTE 2018; 26:149-161. [DOI: 10.1017/s0967199418000047] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
SummaryThe objective of the study was to investigate the effect of l-ergothioneine (l-erg) (5 mM or 10 mM) supplementation in maturation medium on the developmental potential and OCTN1-dependant l-erg-mediated (10 mM) change in mRNA abundance of apoptotic (Bcl2, Bax, Casp3 and PCNA) and antioxidant (GPx, SOD1, SOD2 and CAT) genes in sheep oocytes and developmental stages of embryos produced in vitro. Oocytes matured with l-erg (10 mM) reduced their embryo toxicity by decreasing intracellular ROS and increasing intracellular GSH in matured oocytes that in turn improved developmental potential, resulting in significantly (P < 0.05) higher percentages of cleavage (53.72% vs 38.86, 46.56%), morulae (34.36% vs 20.62, 25.84%) and blastocysts (14.83% vs 6.98, 9.26%) compared with other lower concentrations (0 mM and 5 mM) of l-erg without change in maturation rate. l-Erg (10 mM) treatment did not influence the mRNA abundance of the majority of apoptotic and antioxidant genes studied in the matured oocytes and developmental stages of embryo. A gene expression study found that the SLC22A4 gene that encodes OCTN1, an integral membrane protein and specific transporter of l-erg was not expressed in oocytes and developmental stages of embryos. Therefore it was concluded from the study that although there was improvement in the developmental potential of sheep embryos by l-erg supplementation in maturation medium, there was no change in the expression of the majority of the genes studied due to the absence of the SLC22A4 gene in oocytes and embryos that encode OCTN1, which is responsible for transportation of l-erg across the membrane to alter gene expression.
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Tang RMY, Cheah IKM, Yew TSK, Halliwell B. Distribution and accumulation of dietary ergothioneine and its metabolites in mouse tissues. Sci Rep 2018; 8:1601. [PMID: 29371632 PMCID: PMC5785509 DOI: 10.1038/s41598-018-20021-z] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 01/11/2018] [Indexed: 01/31/2023] Open
Abstract
L-ergothioneine (ET) is a diet-derived amino acid that accumulates at high concentrations in animals and humans. Numerous studies have highlighted its antioxidant abilities in vitro, and possible cytoprotective capabilities in vivo. We investigated the uptake and distribution of ET in various organs by a highly sensitive and specific liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) technique, both before and after oral administration of pure ET (35 and 70 mg/kg/day for 1, 7, and 28 days) to male C57BL6J mice. ET primarily concentrates in the liver and whole blood, and also in spleen, kidney, lung, heart, intestines, eye, and brain tissues. Strong correlations were found between ET and its putative metabolites - hercynine, ET-sulfonate (ET-SO3H), and S-methyl ET. Hercynine accumulates in the brain after prolonged ET administration. This study demonstrates the uptake and distribution of ET and provides a foundation for future studies with ET to target oxidative damage in a range of tissues in human diseases.
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Affiliation(s)
- Richard Ming Yi Tang
- National University of Singapore Graduate School for Integrative Sciences and Engineering, Singapore, Singapore
| | - Irwin Kee-Mun Cheah
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 28 Medical Drive, Singapore, Singapore
| | - Terry Shze Keong Yew
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 28 Medical Drive, Singapore, Singapore
| | - Barry Halliwell
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 28 Medical Drive, Singapore, Singapore.
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Abstract
Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
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Affiliation(s)
- Anton Ivanyuk
- Division of Clinical Pharmacology, Lausanne University Hospital (CHUV), Bugnon 17, 1011, Lausanne, Switzerland.
| | - Françoise Livio
- Division of Clinical Pharmacology, Lausanne University Hospital (CHUV), Bugnon 17, 1011, Lausanne, Switzerland
| | - Jérôme Biollaz
- Division of Clinical Pharmacology, Lausanne University Hospital (CHUV), Bugnon 17, 1011, Lausanne, Switzerland
| | - Thierry Buclin
- Division of Clinical Pharmacology, Lausanne University Hospital (CHUV), Bugnon 17, 1011, Lausanne, Switzerland
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Al-Enazy S, Ali S, Albekairi N, El-Tawil M, Rytting E. Placental control of drug delivery. Adv Drug Deliv Rev 2017; 116:63-72. [PMID: 27527665 DOI: 10.1016/j.addr.2016.08.002] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 07/25/2016] [Accepted: 08/04/2016] [Indexed: 01/04/2023]
Abstract
The placenta serves as the interface between the maternal and fetal circulations and regulates the transfer of oxygen, nutrients, and waste products. When exogenous substances are present in the maternal bloodstream-whether from environmental contact, occupational exposure, medication, or drug abuse-the extent to which this exposure affects the fetus is determined by transport and biotransformation processes in the placental barrier. Advances in drug delivery strategies are expected to improve the treatment of maternal and fetal diseases encountered during pregnancy.
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34
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Multiple drug transporters mediate the placental transport of sulpiride. Arch Toxicol 2017; 91:3873-3884. [DOI: 10.1007/s00204-017-2008-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 06/01/2017] [Indexed: 01/15/2023]
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35
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Drenberg CD, Gibson AA, Pounds SB, Shi L, Rhinehart DP, Li L, Hu S, Du G, Nies AT, Schwab M, Pabla N, Blum W, Gruber TA, Baker SD, Sparreboom A. OCTN1 Is a High-Affinity Carrier of Nucleoside Analogues. Cancer Res 2017; 77:2102-2111. [PMID: 28209616 DOI: 10.1158/0008-5472.can-16-2548] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 01/06/2017] [Accepted: 01/24/2017] [Indexed: 11/16/2022]
Abstract
Resistance to xenobiotic nucleosides used to treat acute myeloid leukemia (AML) and other cancers remains a major obstacle to clinical management. One process suggested to participate in resistance is reduced uptake into tumor cells via nucleoside transporters, although precise mechanisms are not understood. Through transcriptomic profiling, we determined that low expression of the ergothioneine transporter OCTN1 (SLC22A4; ETT) strongly predicts poor event-free survival and overall survival in multiple cohorts of AML patients receiving treatment with the cytidine nucleoside analogue cytarabine. Cell biological studies confirmed OCTN1-mediated transport of cytarabine and various structurally related cytidine analogues, such as 2'deoxycytidine and gemcitabine, occurs through a saturable process that is highly sensitive to inhibition by the classic nucleoside transporter inhibitors dipyridamole and nitrobenzylmercaptopurine ribonucleoside. Our findings have immediate clinical implications given the potential of the identified transport system to help refine strategies that could improve patient survival across multiple cancer types where nucleoside analogues are used in cancer treatment. Cancer Res; 77(8); 2102-11. ©2017 AACR.
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Affiliation(s)
- Christina D Drenberg
- Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Alice A Gibson
- Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Stanley B Pounds
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Lei Shi
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Dena P Rhinehart
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Lie Li
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Shuiying Hu
- Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Guoqing Du
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Anne T Nies
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,University of Tübingen, Tübingen, Germany
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,Department of Clinical Pharmacology, University Hospital, Tübingen, Germany
| | - Navjotsingh Pabla
- Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - William Blum
- Division of Hematology, The Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Tanja A Gruber
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Sharyn D Baker
- Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio.
| | - Alex Sparreboom
- Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio.
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Turck D, Bresson J, Burlingame B, Dean T, Fairweather‐Tait S, Heinonen M, Hirsch‐Ernst KI, Mangelsdorf I, McArdle HJ, Naska A, Neuhäuser‐Berthold M, Nowicka G, Pentieva K, Sanz Y, Siani A, Sjödin A, Stern M, Tomé D, Vinceti M, Willatts P, Engel K, Marchelli R, Pöting A, Poulsen M, Schlatter J, Ackerl R, van Loveren H. Safety of synthetic l‐ergothioneine (Ergoneine®) as a novel food pursuant to Regulation (EC) No 258/97. EFSA J 2016. [DOI: 10.2903/j.efsa.2016.4629] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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Frigeni M, Iacobazzi F, Yin X, Longo N. Wide tolerance to amino acids substitutions in the OCTN1 ergothioneine transporter. Biochim Biophys Acta Gen Subj 2016; 1860:1334-42. [PMID: 26994919 DOI: 10.1016/j.bbagen.2016.03.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 02/24/2016] [Accepted: 03/15/2016] [Indexed: 12/30/2022]
Abstract
BACKGROUND Organic cation transporters transfer solutes with a positive charge across the plasma membrane. The novel organic cation transporter 1 (OCTN1) and 2 (OCTN2) transport ergothioneine and carnitine, respectively. Mutations in the SLC22A5 gene encoding OCTN2 cause primary carnitine deficiency, a recessive disorders resulting in low carnitine levels and defective fatty acid oxidation. Variations in the SLC22A4 gene encoding OCTN1 are associated with rheumatoid arthritis and Crohn disease. METHODS Here we evaluate the functional properties of the OCTN1 transporter using chimeric transporters constructed by fusing different portion of the OCTN1 and OCTN2 cDNAs. Their relative abundance and subcellular distribution was evaluated through western blot analysis and confocal microscopy. RESULTS Substitutions of the C-terminal portion of OCTN1 with the correspondent residues of OCTN2 generated chimeric OCTN transporters more active than wild-type OCTN1 in transporting ergothioneine. Additional single amino acid substitutions introduced in chimeric OCTN transporters further increased ergothioneine transport activity. Kinetic analysis indicated that increased transport activity was due to an increased V(max), with modest changes in K(m) toward ergothioneine. CONCLUSIONS Our results indicate that the OCTN1 transporter is tolerant to extensive amino acid substitutions. This is in sharp contrast to the OCTN2 carnitine transporter that has been selected for high functional activity through evolution, with almost all substitutions reducing carnitine transport activity. GENERAL SIGNIFICANCE The widespread tolerance of OCTN1 to amino acid substitutions suggests that the corresponding SLC22A4 gene may have derived from a recent duplication of the SLC22A5 gene and might not yet have a defined physiological role.
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Affiliation(s)
- Marta Frigeni
- Division of Medical Genetics, Departments of Pediatrics and Pathology, University of Utah, Salt Lake City, UT 84108, United States
| | - Francesco Iacobazzi
- Division of Medical Genetics, Departments of Pediatrics and Pathology, University of Utah, Salt Lake City, UT 84108, United States; Department of Basic Medical Sciences, University of Bari, Policlinico, I-70124 Bari, Italy
| | - Xue Yin
- Division of Medical Genetics, Departments of Pediatrics and Pathology, University of Utah, Salt Lake City, UT 84108, United States
| | - Nicola Longo
- Division of Medical Genetics, Departments of Pediatrics and Pathology, University of Utah, Salt Lake City, UT 84108, United States.
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Nickel S, Clerkin CG, Selo MA, Ehrhardt C. Transport mechanisms at the pulmonary mucosa: implications for drug delivery. Expert Opin Drug Deliv 2016; 13:667-90. [DOI: 10.1517/17425247.2016.1140144] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Sabrina Nickel
- School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Caoimhe G. Clerkin
- School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Mohammed Ali Selo
- School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- Faculty of Pharmacy, Kufa University, Al-Najaf, Iraq
| | - Carsten Ehrhardt
- School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
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39
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Ingoglia F, Visigalli R, Rotoli BM, Barilli A, Riccardi B, Puccini P, Dall'Asta V. Functional activity of L-carnitine transporters in human airway epithelial cells. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2015; 1858:210-9. [PMID: 26607009 DOI: 10.1016/j.bbamem.2015.11.013] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 10/21/2015] [Accepted: 11/18/2015] [Indexed: 12/30/2022]
Abstract
Carnitine plays a physiologically important role in the β-oxidation of fatty acids, facilitating the transport of long-chain fatty acids across the inner mitochondrial membrane. Distribution of carnitine within the body tissues is mainly performed by novel organic cation transporter (OCTN) family, including the isoforms OCTN1 (SLC22A4) and OCTN2 (SLC22A5) expressed in human. We performed here a characterization of carnitine transport in human airway epithelial cells A549, Calu-3, NCl-H441, and BEAS-2B, by means of an integrated approach combining data of mRNA/protein expression with the kinetic and inhibition analyses of L-[(3)H]carnitine transport. Carnitine uptake was strictly Na(+)-dependent in all cell models. In A549 and BEAS-2B cells, carnitine uptake was mediated by one high-affinity component (Km<2 μM) identifiable with OCTN2. In both these cell models, indeed, carnitine uptake was maximally inhibited by betaine and strongly reduced by SLC22A5/OCTN2 silencing. Conversely, Calu-3 and NCl-H441 exhibited both a high (Km~20 μM) and a low affinity (Km>1 mM) transport component. While the high affinity component is identifiable with OCTN2, the low affinity uptake is mediated by ATB(0,+), a Na(+), and Cl(-)-coupled transport system for neutral and cationic amino acids, as demonstrated by the inhibition by leucine and arginine, as well as by SLC6A14/ATB(0,+) silencing. The presence of this transporter leads to a massive accumulation of carnitine inside the cells and may be of peculiar relevance in pathologic conditions of carnitine deficiency, such as those associated to OCTN2 defects.
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Affiliation(s)
- Filippo Ingoglia
- Dept. of Biomedical, Biotechnological and Translational Sciences (SBiBiT), University of Parma, Via Volturno 39, 43125 Parma, Italy
| | - Rossana Visigalli
- Dept. of Biomedical, Biotechnological and Translational Sciences (SBiBiT), University of Parma, Via Volturno 39, 43125 Parma, Italy
| | - Bianca Maria Rotoli
- Dept. of Biomedical, Biotechnological and Translational Sciences (SBiBiT), University of Parma, Via Volturno 39, 43125 Parma, Italy
| | - Amelia Barilli
- Dept. of Biomedical, Biotechnological and Translational Sciences (SBiBiT), University of Parma, Via Volturno 39, 43125 Parma, Italy
| | - Benedetta Riccardi
- Preclinical Pharmacokinetics, Biochemistry & Metabolism Dept., Chiesi Farmaceutici, Largo F. Belloli 11/A, 43122 Parma, Italy
| | - Paola Puccini
- Preclinical Pharmacokinetics, Biochemistry & Metabolism Dept., Chiesi Farmaceutici, Largo F. Belloli 11/A, 43122 Parma, Italy
| | - Valeria Dall'Asta
- Dept. of Biomedical, Biotechnological and Translational Sciences (SBiBiT), University of Parma, Via Volturno 39, 43125 Parma, Italy.
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Amniotic fluid l-ergothioneine concentrations in pregnant sheep after natural mating and transfer of vitrified/thawed in-vitro produced embryos. Res Vet Sci 2015; 102:238-41. [DOI: 10.1016/j.rvsc.2015.09.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 08/26/2015] [Accepted: 09/01/2015] [Indexed: 12/18/2022]
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41
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Tega Y, Kubo Y, Yuzurihara C, Akanuma SI, Hosoya KI. Carrier-Mediated Transport of Nicotine Across the Inner Blood–Retinal Barrier: Involvement of a Novel Organic Cation Transporter Driven by an Outward H+ Gradient. J Pharm Sci 2015; 104:3069-75. [DOI: 10.1002/jps.24453] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Revised: 03/19/2015] [Accepted: 03/24/2015] [Indexed: 12/11/2022]
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Walsh DR, Nolin TD, Friedman PA. Drug Transporters and Na+/H+ Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins. Pharmacol Rev 2015; 67:656-80. [PMID: 26092975 PMCID: PMC4485015 DOI: 10.1124/pr.115.010728] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Drug transporters govern the absorption, distribution, and elimination of pharmacologically active compounds. Members of the solute carrier and ATP binding-cassette drug transporter family mediate cellular drug uptake and efflux processes, thereby coordinating the vectorial movement of drugs across epithelial barriers. To exert their physiologic and pharmacological function in polarized epithelia, drug transporters must be targeted and stabilized to appropriate regions of the cell membrane (i.e., apical versus basolateral). Despite the critical importance of drug transporter membrane targeting, the mechanisms that underlie these processes are largely unknown. Several clinically significant drug transporters possess a recognition sequence that binds to PSD-95/Drosophila discs large/ZO-1 (PDZ) proteins. PDZ proteins, such as the Na(+)/H(+) exchanger regulatory factor (NHERF) family, act to stabilize and organize membrane targeting of multiple transmembrane proteins, including many clinically relevant drug transporters. These PDZ proteins are normally abundant at apical membranes, where they tether membrane-delimited transporters. NHERF expression is particularly high at the apical membrane in polarized tissue such as intestinal, hepatic, and renal epithelia, tissues important to drug disposition. Several recent studies have highlighted NHERF proteins as determinants of drug transporter function secondary to their role in controlling membrane abundance and localization. Mounting evidence strongly suggests that NHERF proteins may have clinically significant roles in pharmacokinetics and pharmacodynamics of several pharmacologically active compounds and may affect drug action in cancer and chronic kidney disease. For these reasons, NHERF proteins represent a novel class of post-translational mediators of drug transport and novel targets for new drug development.
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Affiliation(s)
- Dustin R Walsh
- Laboratory for G Protein-Coupled Receptor Biology, Department of Pharmacology and Chemical Biology, and Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (P.A.F.); and Center for Clinical Pharmaceutical Sciences, Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania (D.R.W., T.D.N.)
| | - Thomas D Nolin
- Laboratory for G Protein-Coupled Receptor Biology, Department of Pharmacology and Chemical Biology, and Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (P.A.F.); and Center for Clinical Pharmaceutical Sciences, Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania (D.R.W., T.D.N.)
| | - Peter A Friedman
- Laboratory for G Protein-Coupled Receptor Biology, Department of Pharmacology and Chemical Biology, and Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (P.A.F.); and Center for Clinical Pharmaceutical Sciences, Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania (D.R.W., T.D.N.)
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Mohamed LA, Kaddoumi A. Tacrine sinusoidal uptake and biliary excretion in sandwich-cultured primary rat hepatocytes. JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES 2015; 17:427-38. [PMID: 25224352 DOI: 10.18433/j3801t] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
PURPOSE. The knowledge of hepatic disposition kinetics of tacrine, a first cholinesterase inhibitor was approved by FDA for the treatment of Alzheimer's disease (AD), would help to understand its hepatotoxicity, its therapeutic effect, and improve the management of patients with AD. The current study aims to characterize tacrine hepatic transport kinetics and study the role of organic cation transporters (OCTs), P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP2) in tacrine sinusoidal uptake and biliary excretion. METHODS. Modulation of tacrine hepatic uptake and efflux, biliary excretion index (BEI%), were performed in sandwich-cultured primary rat hepatocytes (SCHs) using transporters inhibitors. Conformation of the integrity of SCHs model was established by capturing images with light-contrast and fluorescence microscopy. RESULTS. Tacrine uptake in SCHs was carrier-mediated process and saturable with apparent Km of 31.5±9.6 µM and Vmax of 908±72 pmol/min/mg protein. Tetraethyl ammonium (TEA), cimetidine and verapamil significantly reduced tacrine uptake with more pronounced effect observed with verapamil which caused 3-fold reduction in tacrine uptake, indicating role for OCTs. Tacrine has a biliary excretion in SCHs with maximum BEI% value of 22.9±1.9% at 10 min of incubation. Addition of MK571 and valspodar decreased the BEI% of tacrine by 40 and 60% suggesting roles for canalicular MRP2 and P-gp, respectively. CONCLUSIONS. Our results show that in addition to metabolism, tacrine hepatic disposition is carrier-mediated process mediated by sinusoidal OCTs, and canalicular MRP2 and P-gp.
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Affiliation(s)
| | - Amal Kaddoumi
- Department of Basic Pharmaceutical Science, School of Pharmacy, University of Louisiana at Monroe. 1800 Bienville Dr., Monroe, LA
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Bhowmik A, Khan R, Ghosh MK. Blood brain barrier: a challenge for effectual therapy of brain tumors. BIOMED RESEARCH INTERNATIONAL 2015; 2015:320941. [PMID: 25866775 PMCID: PMC4383356 DOI: 10.1155/2015/320941] [Citation(s) in RCA: 187] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Revised: 10/27/2014] [Accepted: 11/04/2014] [Indexed: 01/01/2023]
Abstract
Brain tumors are one of the most formidable diseases of mankind. They have only a fair to poor prognosis and high relapse rate. One of the major causes of extreme difficulty in brain tumor treatment is the presence of blood brain barrier (BBB). BBB comprises different molecular components and transport systems, which in turn create efflux machinery or hindrance for the entry of several drugs in brain. Thus, along with the conventional techniques, successful modification of drug delivery and novel therapeutic strategies are needed to overcome this obstacle for treatment of brain tumors. In this review, we have elucidated some critical insights into the composition and function of BBB and along with it we have discussed the effective methods for delivery of drugs to the brain and therapeutic strategies overcoming the barrier.
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Affiliation(s)
- Arijit Bhowmik
- Signal Transduction in Cancer and Stem Cells Laboratory, Division of Cancer Biology and Inflammatory Disorder, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), 4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700 032, India
| | - Rajni Khan
- Signal Transduction in Cancer and Stem Cells Laboratory, Division of Cancer Biology and Inflammatory Disorder, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), 4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700 032, India
| | - Mrinal Kanti Ghosh
- Signal Transduction in Cancer and Stem Cells Laboratory, Division of Cancer Biology and Inflammatory Disorder, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), 4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700 032, India
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Han TU, Lee HS, Kang C, Bae SC. Association of joint erosion with SLC22A4 gene polymorphisms inconsistently associated with rheumatoid arthritis susceptibility. Autoimmunity 2015; 48:313-7. [PMID: 25707686 DOI: 10.3109/08916934.2015.1016219] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Two single-nucleotide polymorphisms (SNPs) in SLC22A4 encoding an organic cation/zwitterion transporter protein, rs2073838 (commonly called slc2F1) and rs3792876 (slc2F2), had been associated with susceptibility to rheumatoid arthritis (RA) in two Japanese and one recent Chinese studies but not in other two Japanese and six Caucasian studies. In this study, the two SNPs were genotyped for 2313 Korean participants and their associations with RA susceptibility and severity were examined. SNP association with RA susceptibility was tested among 1304 RA patients and 1009 healthy controls, and association with joint erosion among 1063 erosive and 241 non-erosive RA patients. Meta-analysis for RA susceptibility association was additionally performed using 10 previous studies and the current one. The two SNPs were almost perfectly correlated with each other (r(2 )= 0.98), and therefore only slc2F1 was tested for association. RA susceptibility association was not found in Koreans (p = 0.93), but still significant in meta-analysis of six Asian studies including this Korean study (p = 0.00036, odds ratio = 1.1) or all 11 studies additionally including five Caucasian studies (p = 0.00021, odds ratio = 1.1). In contrast, an association was found for RA severity in Koreans. The minor allele A was marginally associated with 1.5-fold increased risk of joint erosion among RA patients afflicted for ≤11 years (p = 0.025) or ≤7 years (p = 0.029), though not among patients with longer-standing RA. Accordingly, SLC22A4 was associated with joint erosion in not-very-longstanding RA, although RA susceptibility association was weak and its clinical significance was uncertain.
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Affiliation(s)
- Tae-Un Han
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology , Daejeon , Korea and
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46
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Sanchez-Covarrubias L, Slosky LM, Thompson BJ, Davis TP, Ronaldson PT. Transporters at CNS barrier sites: obstacles or opportunities for drug delivery? Curr Pharm Des 2014; 20:1422-49. [PMID: 23789948 DOI: 10.2174/13816128113199990463] [Citation(s) in RCA: 166] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Accepted: 06/18/2013] [Indexed: 01/11/2023]
Abstract
The blood-brain barrier (BBB) and blood-cerebrospinal fluid (BCSF) barriers are critical determinants of CNS homeostasis. Additionally, the BBB and BCSF barriers are formidable obstacles to effective CNS drug delivery. These brain barrier sites express putative influx and efflux transporters that precisely control permeation of circulating solutes including drugs. The study of transporters has enabled a shift away from "brute force" approaches to delivering drugs by physically circumventing brain barriers towards chemical approaches that can target specific compounds of the BBB and/or BCSF barrier. However, our understanding of transporters at the BBB and BCSF barriers has primarily focused on understanding efflux transporters that efficiently prevent drugs from attaining therapeutic concentrations in the CNS. Recently, through the characterization of multiple endogenously expressed uptake transporters, this paradigm has shifted to the study of brain transporter targets that can facilitate drug delivery (i.e., influx transporters). Additionally, signaling pathways and trafficking mechanisms have been identified for several endogenous BBB/BCSF transporters, thereby offering even more opportunities to understand how transporters can be exploited for optimization of CNS drug delivery. This review presents an overview of the BBB and BCSF barrier as well as the many families of transporters functionally expressed at these barrier sites. Furthermore, we present an overview of various strategies that have been designed and utilized to deliver therapeutic agents to the brain with a particular emphasis on those approaches that directly target endogenous BBB/BCSF barrier transporters.
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Affiliation(s)
| | | | | | | | - Patrick T Ronaldson
- Department of Medical Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Avenue, P.O. Box 245050, Tucson, AZ, 85724-5050.
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47
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Kell DB, Oliver SG. How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion. Front Pharmacol 2014; 5:231. [PMID: 25400580 PMCID: PMC4215795 DOI: 10.3389/fphar.2014.00231] [Citation(s) in RCA: 115] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Accepted: 09/29/2014] [Indexed: 12/12/2022] Open
Abstract
One approach to experimental science involves creating hypotheses, then testing them by varying one or more independent variables, and assessing the effects of this variation on the processes of interest. We use this strategy to compare the intellectual status and available evidence for two models or views of mechanisms of transmembrane drug transport into intact biological cells. One (BDII) asserts that lipoidal phospholipid Bilayer Diffusion Is Important, while a second (PBIN) proposes that in normal intact cells Phospholipid Bilayer diffusion Is Negligible (i.e., may be neglected quantitatively), because evolution selected against it, and with transmembrane drug transport being effected by genetically encoded proteinaceous carriers or pores, whose “natural” biological roles, and substrates are based in intermediary metabolism. Despite a recent review elsewhere, we can find no evidence able to support BDII as we can find no experiments in intact cells in which phospholipid bilayer diffusion was either varied independently or measured directly (although there are many papers where it was inferred by seeing a covariation of other dependent variables). By contrast, we find an abundance of evidence showing cases in which changes in the activities of named and genetically identified transporters led to measurable changes in the rate or extent of drug uptake. PBIN also has considerable predictive power, and accounts readily for the large differences in drug uptake between tissues, cells and species, in accounting for the metabolite-likeness of marketed drugs, in pharmacogenomics, and in providing a straightforward explanation for the late-stage appearance of toxicity and of lack of efficacy during drug discovery programmes despite macroscopically adequate pharmacokinetics. Consequently, the view that Phospholipid Bilayer diffusion Is Negligible (PBIN) provides a starting hypothesis for assessing cellular drug uptake that is much better supported by the available evidence, and is both more productive and more predictive.
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Affiliation(s)
- Douglas B Kell
- School of Chemistry, The University of Manchester Manchester, UK ; Manchester Institute of Biotechnology, The University of Manchester Manchester, UK
| | - Stephen G Oliver
- Department of Biochemistry, University of Cambridge Cambridge, UK ; Cambridge Systems Biology Centre, University of Cambridge Cambridge, UK
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48
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Manzetti S, Zhang J, van der Spoel D. Thiamin Function, Metabolism, Uptake, and Transport. Biochemistry 2014; 53:821-35. [DOI: 10.1021/bi401618y] [Citation(s) in RCA: 195] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Sergio Manzetti
- Uppsala
Center for Computational Chemistry, Science for Life Laboratory, Department
for Cell and Molecular Biology, University of Uppsala, Box 596, 751
24 Uppsala, Sweden
- Fjordforsk A.S., Fresvik 6896, Norway
| | - Jin Zhang
- Uppsala
Center for Computational Chemistry, Science for Life Laboratory, Department
for Cell and Molecular Biology, University of Uppsala, Box 596, 751
24 Uppsala, Sweden
- Department
of Chemistry, Zhejiang University, Hangzhou 310027, China
| | - David van der Spoel
- Uppsala
Center for Computational Chemistry, Science for Life Laboratory, Department
for Cell and Molecular Biology, University of Uppsala, Box 596, 751
24 Uppsala, Sweden
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Abstract
Organic anions and cations (OAs and OCs, respectively) comprise an extraordinarily diverse array of compounds of physiological, pharmacological, and toxicological importance. The kidney, primarily the renal proximal tubule, plays a critical role in regulating the plasma concentrations of these organic electrolytes and in clearing the body of potentially toxic xenobiotics agents, a process that involves active, transepithelial secretion. This transepithelial transport involves separate entry and exit steps at the basolateral and luminal aspects of renal tubular cells. Basolateral and luminal OA and OC transport reflects the concerted activity of a suite of separate proteins arranged in parallel in each pole of proximal tubule cells. The cloning of multiple members of several distinct transport families, the subsequent characterization of their activity, and their subcellular localization within distinct regions of the kidney, now allows the development of models describing the molecular basis of the renal secretion of OAs and OCs. New information on naturally occurring genetic variation of many of these processes provides insight into the basis of observed variability of drug efficacy and unwanted drug-drug interactions in human populations. The present review examines recent work on these issues.
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Affiliation(s)
- Ryan M Pelis
- Novartis Pharmaceuticals Corp., Translational Sciences, East Hanover, New Jersey, USA
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50
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Mehta DC, Short JL, Nicolazzo JA. Memantine Transport across the Mouse Blood–Brain Barrier Is Mediated by a Cationic Influx H+ Antiporter. Mol Pharm 2013; 10:4491-8. [DOI: 10.1021/mp400316e] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Dharmini C. Mehta
- Drug Delivery, Disposition and
Dynamics, and ‡Drug Discovery Biology, Monash Institute
of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Jennifer L. Short
- Drug Delivery, Disposition and
Dynamics, and ‡Drug Discovery Biology, Monash Institute
of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Joseph A. Nicolazzo
- Drug Delivery, Disposition and
Dynamics, and ‡Drug Discovery Biology, Monash Institute
of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
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