Molecular mechanisms of resistance and toxicity associated with platinating agents.

There are two classes of glucose transporters involved in glucose homeostasis in the body, the facilitated transporters or uniporters (GLUTs) and the active transporters or symporters (SGLTs). The ...

Biology of Human Sodium Glucose Transporters

The body is equipped with broad-specificity transporters for the excretion and distribution of endogeneous organic cations and for the uptake, elimination and distribution of cationic drugs, toxins and environmental waste products. This group of transporters consists of the electrogenic cation transporters OCT1-3 (SLC22A1-3), the cation and carnitine transporters OCTN1 (SLC22A4), OCTN2 (SLC22A5) and OCT6 (SLC22A16), and the proton/cation antiporters MATE1, MATE2-K and MATE2-B. The transporters show broadly overlapping sites of expression in many tissues such as small intestine, liver, kidney, heart, skeletal muscle, placenta, lung, brain, cells of the immune system, and tumors. In epithelial cells they may be located in the basolateral or luminal membranes. Transcellular cation movement in small intestine, kidney and liver is mediated by the combined action of electrogenic OCT-type uptake systems and MATE-type efflux transporters that operate as cation/proton antiporters. Recent data showed that OCT-type transporters participate in the regulation of extracellular concentrations of neurotransmitters in brain, mediate the release of acetylcholine in non-neuronal cholinergic reactions, and are critically involved in the regulation of histamine release from basophils. The recent identification of polymorphisms in human OCTs and OCTNs allows the identification of patients with an increased risk for adverse drug reactions. Transport studies with expressed OCTs will help to optimize pharmacokinetics during development of new drugs.

Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications.

Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting β polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) α and β] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2.

Previously we cloned a polyspecific transporter from rat (rOCT1) that is expressed in renal proximal tubules and hepatocytes and mediates electrogenic uptake of organic cations with different molecular structures. Recently a homologous transporter from rat kidney (rOCT2) was cloned but not characterized in detail. We report cloning and characterization of two homologous transporters from man (hOCT1 and hOCT2) displaying approximately 80% amino acid identity to rOCT1 and rOCT2, respectively. Northern blots showed that hOCT1 is mainly transcribed in liver, while hOCT2 is found in kidney. Using in situ hybridization and immunohistochemistry, expression of hOCT2 was mainly detected in the distal tubule where the transporter is localized at the luminal membrane. After expression in Xenopus laevis oocytes, hOCT1 and hOCT2 mediate tracer influx of N-1-methylnicotinamide (NMN), tetraethylammonium (TEA), and 1-methyl-4-phenylpyridinium (MPP). For cation transport by hOCT2 apparent κm and κi values were determined ...

Cloning and Characterization of Two Human Polyspecific Organic Cation Transporters

Renal excretion and reabsorption of organic cations are mediated by electrogenic and electroneutral organic cation transporters, which belong to a recently discovered family of polyspecific transporters. These transporters are electrogenic and exhibit differences in substrate specificity. In rat, the renal expression of the polyspecific cation transporters rOCT1 and rOCT2 was investigated. By in situ hybridization, significant amounts of both rOCT1 and rOCT2 mRNA were detected in S1, S2, and S3 segments of proximal tubules. By immunohistochemistry, expression of the rOCT1 protein was mainly observed in S1 and S2 segments of proximal tubules, with lower expression levels in the S3 segments. At variance, rOCT2 protein was mainly expressed in the S2 and S3 segments. Both transporters were localized to the basolateral cell membrane. Neither rOCT1 nor rOCT2 was detected in the vasculature, the glomeruli, and nephron segments other than proximal tubules. The data suggest that rOCT1 and rOCT2 are responsible for basolateral cation uptake in the proximal tubule, which represents the first step in cation secretion.

https://www.physiology.org/doi/pdf/10.1152/ajprenal.2000.279.4.F679

Localization of organic cation transporters OCT1 and OCT2 in rat kidney.

In brains of the rabbit, pig, and human, expression of the high-affinity Na + -D-glucose cotransporter SGLT1 and of the protein RS1, which alters the activity of SGLT1, was demonstrated. In situ hybridization showed that SGLT1 and RS1 are transcribed in pyramidal cells of brain cortex and hippocampus and in Purkinje cells of cerebellum. In neurons of pig brain SGLT1 protein was demonstrated by western blotting with synaptosomal membranes and by immunohistochemistry, which showed SGLT1 in pyramidal and Purkinje cells. To test whether SGLT1 in neurons may be activated during increased D-glucose consumption, an epileptic seizure was induced in rat brain, and the uptake of specific nonmetabolized substrates of SGLT1 {[14C]methyl-α-D-glucopyranoside ([ 14 C]AMG)} and of Na + -independent transporters (2-deoxy-D-[ 14 C]glucose ([ 14 C]2-DG)} was analyzed by autoradiography. During the seizure the uptake of AMG and 2-DG was increased in the focus. Within two hours after the seizure 2-DG uptake in the focus returned to normal. In contrast, the AMG uptake in the focus area was still increased 1 day later. The data show that the high-affinity Na + -D-glucose cotransporter SGLT1 is expressed in neurons and can be up-regulated.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1471-4159.1997.69010084.x

Expression of the Na+-d-Glucose Cotransporter SGLT1 in Neurons†

/pdf/polyspecific-cation-transporters-in-the-proximal-tubule-50fk1a9vki.pdf

Polyspecific cation transporters in the proximal tubule.

Patients with chronic inflammatory rheumatic diseases (CIRD) remain underrepresented in receiving vaccinations despite being disproportionately affected by infectious complications.To systematically review the literature regarding vaccination willingness and vaccination hesitancy in CIRD patients with focus on the perspective of patients and physicians.A scoping review was conducted in PUBMED, EMBASE and the Cochrane Library through 2021. Study selection was performed by two independent reviewers, data were extracted using a standardized form and risk of bias was assessed using instruments from the McMaster University. Identified barriers and hurdles were synthesized by categorizing them into the WHO’s Measuring Behavioural and Social Drivers of Vaccination (BeSD) conceptual model.The search yielded 1,644 hits, of which 30 were included (cross-sectional studies (n=27) based on interviews and 3 intervention studies). The majority of studies reported barriers to influenza and pneumococcal vaccination (n=11), or influenza vaccination only (n=9) from the patients perspective. Two studies assessed the attitudes towards COVID-19 vaccinations. Only one study assessed the view of rheumatologists. Patients mainly mentioned behavioral and social factors that negatively influence their willingness to be vaccinated while physicians see deficits in the organization and lack of time as a major barrier. Coverage of domains matched to the BeSD model suggests a lack of awareness of infection risk by both patients and physicians (Figure 1).Figure 1.Coverage of domains matched to the WHO BeSD ModelThe view of vaccination in CIRD patients diverges between patients and rheumatologists. Our results show that in-depth counseling on vaccines is important for patients, whereas physicians need support in implementing specific immunization recommendations. The themes identified provide a starting point for future interventions to improve vaccine rates in CIRD patients.None declared

/pdf/ab1402-facilitators-and-barriers-of-vaccine-uptake-in-3b2qvkf6.pdf

Ulrich Karbach

Papers

Cloning and Characterization of Two Human Polyspecific Organic Cation Transporters

Localization of organic cation transporters OCT1 and OCT2 in rat kidney.

Expression of the Na+-d-Glucose Cotransporter SGLT1 in Neurons†

Polyspecific cation transporters in the proximal tubule.

Ab1402 facilitators and barriers of vaccine uptake in patients with chronic inflammatory rheumatic disease: a scoping review