scholarly journals Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 & 2 and AMP-activated Protein Kinase in the Kidney

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Michael Christensen ◽  
Jonas B. Jensen ◽  
Steen Jakobsen ◽  
Niels Jessen ◽  
Jørgen Frøkiær ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Organic Cation ◽  
Organic Cation Transporters ◽  
Cation Transporters ◽  
Amp Activated Protein Kinase

scholarly journals Metformin Inhibits Human Androgen Production by Regulating Steroidogenic Enzymes HSD3B2 and CYP17A1 and Complex I Activity of the Respiratory Chain

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4354-4366 ◽  
Author(s):  
Andrea Hirsch ◽  
Dagmar Hahn ◽  
Petra Kempná ◽  
Gaby Hofer ◽  
Jean-Marc Nuoffer ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Polycystic Ovary Syndrome ◽  
Respiratory Chain ◽  
Complex I ◽  
Organic Cation ◽  
Polycystic Ovary ◽  
Organic Cation Transporters ◽  
Ovary Syndrome ◽  
Ampk Signaling ◽  
Cation Transporters

Metformin is treatment of choice for the metabolic consequences seen in polycystic ovary syndrome for its insulin-sensitizing and androgen-lowering properties. Yet, the mechanism of action remains unclear. Two potential targets for metformin regulating steroid and glucose metabolism are AMP-activated protein kinase (AMPK) signaling and the complex I of the mitochondrial respiratory chain. Androgen biosynthesis requires steroid enzymes 17α-Hydroxylase/17,20 lyase (CYP17A1) and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2), which are overexpressed in ovarian cells of polycystic ovary syndrome women. Therefore, we aimed to understand how metformin modulates androgen production using NCI-H295R cells as an established model of steroidogenesis. Similar to in vivo situation, metformin inhibited androgen production in NCI cells by decreasing HSD3B2 expression and CYP17A1 and HSD3B2 activities. The effect of metformin on androgen production was dose dependent and subject to the presence of organic cation transporters, establishing an important role of organic cation transporters for metformin's action. Metformin did not affect AMPK, ERK1/2, or atypical protein kinase C signaling. By contrast, metformin inhibited complex I of the respiratory chain in mitochondria. Similar to metformin, direct inhibition of complex I by rotenone also inhibited HSD3B2 activity. In conclusion, metformin inhibits androgen production by mechanisms targeting HSD3B2 and CYP17-lyase. This regulation involves inhibition of mitochondrial complex I but appears to be independent of AMPK signaling.

Transport of Dicationic Drugs Pentamidine and Furamidine by Human Organic Cation Transporters

2008 ◽  
Vol 37 (2) ◽  
pp. 424-430 ◽  
Author(s):  
Xin Ming ◽  
Wujian Ju ◽  
Huali Wu ◽  
Richard R. Tidwell ◽  
James E. Hall ◽  
...  
Keyword(s):  
Organic Cation ◽  
Organic Cation Transporters ◽  
Cation Transporters

Role of organic cation transporters in the ocular disposition of its intravenously injected substrate in rabbits: Implications for ocular drug therapy

2013 ◽  
Vol 116 ◽  
pp. 27-35 ◽  
Author(s):  
Jayabalan Nirmal ◽  
Anju Sirohiwal ◽  
Sundararajan Baskar Singh ◽  
Nihar Ranjan Biswas ◽  
Vasantha Thavaraj ◽  
...  
Keyword(s):  
Drug Therapy ◽  
Organic Cation ◽  
Organic Cation Transporters ◽  
Cation Transporters

The role of organic cation transporters (OCTs) in the transfer of metformin in the dually perfused human placenta

2010 ◽  
Vol 39 (1-3) ◽  
pp. 76-81 ◽  
Author(s):  
Kristiina Tertti ◽  
Ulla Ekblad ◽  
Tuija Heikkinen ◽  
Melissa Rahi ◽  
Tapani Rönnemaa ◽  
...  
Keyword(s):  
Human Placenta ◽  
Organic Cation ◽  
Organic Cation Transporters ◽  
Cation Transporters

Abstract 14035: Renal Tubular Secretion and Cardiac Distribution of Dofetilide is Dependent on MATE1 Function

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Muhammad Erfan Uddin ◽  
Yan Jin ◽  
Alice A Gibson ◽  
Ingrid M Bonilla ◽  
Cynthia A Carnes ◽  
...  
Keyword(s):  
Organic Cation ◽  
Tubular Secretion ◽  
Hek293 Cells ◽  
Delayed Rectifier ◽  
Organic Cation Transporters ◽  
Wild Type ◽  
Renal Tubular Secretion ◽  
Cation Transporters ◽  
Renal Tubular

Introduction: Dofetilide is a delayed rectifier potassium channel inhibitor used to treat patients with atrial fibrillation and flutter, and its use is associated with a risk of QT prolongation and Torsades de Pointes . The mechanisms involved in dofetilide’s renal tubular secretion and its uptake into cardiomyocytes remain unknown. Previously reported drug-drug interaction (DDI) studies suggest the involvement of organic cation transporters. Here, we investigated the contribution of organic cation transporters (OCT2 and MATE1) to the pharmacokinetics of dofetilide to gain insight into its DDI potential. Hypothesis: Based on known DDIs with dofetilide, we hypothesize that OCT2 and/or MATE1 play a key role in the inter-individual variability in pharmacokinetics and pharmacodynamics of dofetilide. Methods: In vitro and ex vivo transport kinetics of dofetilide were determined in HEK293 cells stably transfected with OCT2 or MATE1, and in isolated cardiomyocytes, respectively. In vivo studies were performed in wild-type, OCT2-, and MATE1-deficient mice (n=5) receiving dofetilide (5 mg/kg, p.o., 2.5 mg/kg, i.v.), with or without several contraindicated drugs. Dofetilide concentrations in plasma and urine were determined by UPLC-MS/MS. Results: In vitro studies demonstrated that dofetilide is a good substrate of MATE1 but not OCT2. Deficiency of MATE1 was associated with increased plasma concentrations of dofetilide and with a significantly reduced urinary excretion (3-fold in females and 5-fold in males, respectively). Dofetilide accumulation in cardiomyocytes was increased by 2-fold in MATE1-deficient females, and pre-incubation with the MATE1 inhibitor cimetidine significantly reduced dofetilide uptake in wild-type cardiomyocytes. Several contraindicated drugs listed in the dofetilide prescribing information, including cimetidine, ketoconazole, increased dofetilide plasma exposure in wild-type mice by >2.8-fold. Conclusion: Renal secretion of dofetilide is mediated by MATE1 and is highly sensitive to inhibition by many widely used prescription drugs that can cause clinically relevant DDIs. Deficiency of MATE1 also increases accumulation in the heart which may contribute to individual variation in response to dofetilide.

scholarly journals Interaction Profiles of Central Nervous System Active Drugs at Human Organic Cation Transporters 1–3 and Human Plasma Membrane Monoamine Transporter

2021 ◽  
Vol 22 (23) ◽  
pp. 12995
Author(s):  
Thomas J. F. Angenoorth ◽  
Stevan Stankovic ◽  
Marco Niello ◽  
Marion Holy ◽  
Simon D. Brandt ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Plasma Membrane ◽  
Human Plasma ◽  
Organic Cation ◽  
Hek293 Cells ◽  
Monoamine Transporters ◽  
Organic Cation Transporters ◽  
Monoamine Transporter ◽  
Cation Transporters

Many psychoactive compounds have been shown to primarily interact with high-affinity and low-capacity solute carrier 6 (SLC6) monoamine transporters for norepinephrine (NET; norepinephrine transporter), dopamine (DAT; dopamine transporter) and serotonin (SERT; serotonin transporter). Previous studies indicate an overlap between the inhibitory capacities of substances at SLC6 and SLC22 human organic cation transporters (SLC22A1–3; hOCT1–3) and the human plasma membrane monoamine transporter (SLC29A4; hPMAT), which can be classified as high-capacity, low-affinity monoamine transporters. However, interactions between central nervous system active substances, the OCTs, and the functionally-related PMAT have largely been understudied. Herein, we report data from 17 psychoactive substances interacting with the SLC6 monoamine transporters, concerning their potential to interact with the human OCT isoforms and hPMAT by utilizing radiotracer-based in vitro uptake inhibition assays at stably expressing human embryonic kidney 293 cells (HEK293) cells. Many compounds inhibit substrate uptake by hOCT1 and hOCT2 in the low micromolar range, whereas only a few substances interact with hOCT3 and hPMAT. Interestingly, methylphenidate and ketamine selectively interact with hOCT1 or hOCT2, respectively. Additionally, 3,4-methylenedioxymethamphetamine (MDMA) is a potent inhibitor of hOCT1 and 2 and hPMAT. Enantiospecific differences of R- and S-α-pyrrolidinovalerophenone (R- and S-α-PVP) and R- and S-citalopram and the effects of aromatic substituents are explored. Our results highlight the significance of investigating drug interactions with hOCTs and hPMAT, due to their role in regulating monoamine concentrations and xenobiotic clearance.

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