Interaction and Transport of Methamphetamine and its Primary Metabolites by Organic Cation and Multidrug and Toxin Extrusion Transporters.

Methamphetamine is one of the most abused illicit drugs with roughly 1.2 million users in the United States alone. A large portion of methamphetamine and its metabolites is eliminated by the kidney with renal clearance larger than glomerular filtration clearance.

Potent inhibition of human organic cation transporter 2 (hOCT2) by β-carboline alkaloids.

1. Beta-carbolines are indole alkaloids with a wide range of pharmacological and toxicological activities. Beta-carbolines are structurally related to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), a known substrate of organic cation transporters (OCTs).

Impact of Substrate-Dependent Inhibition on Renal Organic Cation Transporters hOCT2 and hMATE1/2-K-Mediated Drug Transport and Intracellular Accumulation.

Renal transporter-mediated drug-drug interactions (DDIs) are of significant clinical concern, as they can adversely impact drug disposition, efficacy, and toxicity. Emerging evidence suggests that human renal organic cation transporter 2 (hOCT2) and multidrug and toxin extrusion proteins 1 and 2-K (hMATE1/2-K) exhibit substrate-dependent inhibition, but their impact on renal drug secretion and intracellular accumulation is unknown. Using metformin and atenolol as the probe substrates, we found that the classic inhibitors (e.

Interspecies comparison of the functional characteristics of plasma membrane monoamine transporter (PMAT) between human, rat and mouse.

Plasma membrane monoamine transporter (PMAT) is a newly discovered monoamine transporter belonging to the equilibrative nucleoside transporter family. Highly expressed in the brain, PMAT represents a major uptake transporter that may play a role in monoamine clearance. Although human PMAT has been functionally characterized at the molecular level, rodent models are often used to evaluate PMAT function in ex vivo and in vivo studies.

Regulation of StAR by the N-terminal Domain and Coinduction of SIK1 and TIS11b/Znf36l1 in Single Cells.

The cholesterol transfer function of steroidogenic acute regulatory protein (StAR) is uniquely integrated into adrenal cells, with mRNA translation and protein kinase A (PKA) phosphorylation occurring at the mitochondrial outer membrane (OMM). The StAR C-terminal cholesterol-binding domain (CBD) initiates mitochondrial intermembrane contacts to rapidly direct cholesterol to Cyp11a1 in the inner membrane (IMM). The conserved StAR N-terminal regulatory domain (NTD) includes a leader sequence targeting the CBD to OMM complexes that initiate cholesterol transfer.

Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins.

Atenolol is a β-blocker widely used in the treatment of hypertension. Atenolol is cleared predominantly by the kidney by both glomerular filtration and active secretion, but the molecular mechanisms involved in its renal secretion are unclear. Using a panel of human embryonic kidney cell lines stably expressing human organic cation transporter (hOCT) 1-3, human organic anion transporter (hOAT) 1, hOAT3, human multidrug and toxin extrusion protein (hMATE) 1, and hMATE2-K, we found that atenolol interacted with both organic cation and anion transporters.

Potent and Selective Inhibition of Plasma Membrane Monoamine Transporter by HIV Protease Inhibitors.

Plasma membrane monoamine transporter (PMAT) is a major uptake-2 monoamine transporter that shares extensive substrate and inhibitor overlap with organic cation transporters 1-3 (OCT1-3). Currently, there are no PMAT-specific inhibitors available that can be used in in vitro and in vivo studies to differentiate between PMAT and OCT activities. In this study, we showed that IDT307 (4-(4-(dimethylamino)phenyl)-1-methylpyridinium iodide), a fluorescent analog of 1-methyl-4-phenylpyridinium (MPP+), is a transportable substrate for PMAT and that IDT307-based fluorescence assay can be used to rapidly identify and characterize PMAT inhibitors.

Taste of a pill: organic cation transporter-3 (OCT3) mediates metformin accumulation and secretion in salivary glands.

Drug-induced taste disturbance is a common adverse drug reaction often triggered by drug secretion into saliva. Very little is known regarding the molecular mechanisms underlying salivary gland transport of xenobiotics, and most drugs are assumed to enter saliva by passive diffusion. In this study, we demonstrate that salivary glands selectively and highly express OCT3 (organic cation transporter-3), a polyspecific drug transporter in the solute carrier 22 family.

Recipient pretransplant inosine monophosphate dehydrogenase activity in nonmyeloablative hematopoietic cell transplantation.

Mycophenolic acid, the active metabolite of mycophenolate mofetil (MMF), inhibits inosine monophosphate dehydrogenase (IMPDH) activity. IMPDH is the rate-limiting enzyme involved in de novo synthesis of guanosine nucleotides and catalyzes the oxidation of inosine 5'-monophosphate to xanthosine 5'-monophosphate (XMP). We developed a highly sensitive liquid chromatography-mass spectrometry method to quantitate XMP concentrations in peripheral blood mononuclear cells (PMNCs) isolated from the recipient pretransplant and used this method to determine IMPDH activity in 86 nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) patients.

Impaired monoamine and organic cation uptake in choroid plexus in mice with targeted disruption of the plasma membrane monoamine transporter (Slc29a4) gene.

The choroid plexus (CP) forms the blood-cerebrospinal fluid (CSF) barrier and protects the brain from circulating metabolites, drugs, and toxins. The plasma membrane monoamine transporter (PMAT, SLC29A4) is a new polyspecific organic cation transporter that transports a wide variety of organic cations including biogenic amines, cationic drugs, and neurotoxins. PMAT is known to be expressed in the CP, but its specific role in CP transport of organic cations has not been clearly defined.

Molecular analysis and structure-activity relationship modeling of the substrate/inhibitor interaction site of plasma membrane monoamine transporter.

Plasma membrane monoamine transporter (PMAT) is a new polyspecific transporter that interacts with a wide range of structurally diverse organic cations. To map the physicochemical descriptors of cationic compounds that allow interaction with PMAT, we systematically analyzed the interactions between PMAT and three series of structural analogs of known organic cation substrates including phenylalkylamines, n-tetraalkylammonium (n-TAA) compounds, and β-carbolines. Our results showed that phenylalkylamines with a distance between the aromatic ring and the positively charged amine nitrogen atom of ∼6.

cAMP stimulation of StAR expression and cholesterol metabolism is modulated by co-expression of labile suppressors of transcription and mRNA turnover.

The steroidogenic acute regulatory (StAR) protein is generated in rodents from 1.6 kb and 3.5 kb mRNA formed by alternative polyadenylation.

Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3.

The plasma membrane monoamine transporter (PMAT) and organic cation transporter 3 (OCT3) are the two most prominent low-affinity, high-capacity (i.e., uptake(2)) transporters for endogenous biogenic amines.

Adenosine transport by plasma membrane monoamine transporter: reinvestigation and comparison with organic cations.

The plasma membrane monoamine transporter (PMAT) belongs to the equilibrative nucleoside transporter family (solute carrier 29) and was alternatively named equilibrative nucleoside transporter 4. Previous studies from our laboratory characterized PMAT as a polyspecific organic cation transporter that minimally interacts with nucleosides. Recently, PMAT-mediated uptake of adenosine (a purine nucleoside) was reported, and the transporter was proposed to function as a dual nucleoside/organic cation transporter.

cAMP-dependent posttranscriptional regulation of steroidogenic acute regulatory (STAR) protein by the zinc finger protein ZFP36L1/TIS11b.

Star is expressed in steroidogenic cells as 3.5- and 1.6-kb transcripts that differ only in their 3'-untranslated regions (3'-UTR).

The predominant cAMP-stimulated 3 x 5 kb StAR mRNA contains specific sequence elements in the extended 3'UTR that confer high basal instability.

cAMP stimulation of rodent steroidogenic cells produces two StAR transcripts, a major 3.5 kb and a minor 1.6 kb mRNA, differing only in their 3' untranslated regions (3' UTR).

Rodent StAR mRNA is substantially regulated by control of mRNA stability through sites in the 3'-untranslated region and through coupling to ongoing transcription.

The steroidogenic acute regulator (StAR) gene is transcribed to 1.6 kb and 3.5 kb mRNAs that differ only through the length of the 3'-untranslated region (3'-UTR).