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Results for “Organic Cation Transporter 1”

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PubMed2003

Organic anion and cation transporters occur in pairs of similar and similarly expressed genes.

Organic anion and cation transporters (OATs, OCTs, OCTNs, and ORCTLs), transmembrane proteins essential to renal xenobiotic excretion, are encoded by a group of related genes. As yet there have been no studies of the transcriptional regulation of this important gene family. While such studies have traditionally been labor-intensive, comparative genomics approaches are now available that have proven reliable guides to critical regulatory elements. We report here the genomic sequencing of murine OAT1 (the cDNA of which was originally cloned by us as NKT) and OAT3 (Roct), and derivation of phylogenetic footprints (evolutionarily conserved non-coding sequences) by comparison to the human genome. We find binding sites within these footprints for several transcription factors implicated in kidney development, including PAX1, PBX, WT1, and HNF1. Additionally, we note that OATs and OCTs occur in the human and mouse genomes as tightly linked pairs (OAT1 and OAT3, UST3 and OAT5, OAT4 and URAT1/RST, OCT1 and 2, OCTN1 and 2, ORCTL3 and 4) that are also close phylogenetic relations, with Flipt1 and 2, and OAT2 the only unpaired family members. Finally, we find that pair-members have similar tissue distributions, suggesting that the pairing might exist to facilitate the co-regulation of the genes within each pair.

5' Flanking Region↗

PubMed2026

Ergothioneine as an emerging food-derived bioactive compound protecting against age-related diseases: issues needing more research.

Ergothioneine (ET) is a chemically stable, tasteless, odorless, highly water-soluble diet-derived compound that is avidly absorbed and retained by the human body using a selective transporter, organic cation transporter novel 1 (often called the ET transporter). A substantial and growing body of evidence supports a role for ET in maintaining human health and protecting against age-related diseases, especially neurodegenerative diseases, and multiple studies indicate that low blood/plasma/serum ET concentrations increase risk of developing age-related diseases. Despite the growing interest in ET, much fundamental work remains to be done to investigate its metabolism, actions (if any) on the genome, lipidome, metabolome, and proteome, intracellular and intercellular transport (especially in the brain), precise mechanisms of cytoprotection, interactions with the microbiome, mycobiome, and human pathogens, and identifying the factors that control body ET levels. This narrative review explores these issues and suggests what research needs to be done to improve our understanding of ET biology.

M. tuberculosis↗

PubMed1978

Hepatic disposition and biliary excretion of the organic cations thiazinamium and thiazinamium sulfoxide in rats.

The disappearance from plasma and the excretion in bile of the monoquaternary thiazinamium (administered as the iodide) and one of its polar metabolites, thiazinamium sulfoxide (also administered as the iodide), were studied in the rat after intravenous injection to obtain more information on hepatic transport mechanisms for organic cations. Both compounds exhibited an extremely rapid plasma disappearance, partly due to a rapid liver uptake. After injection of thiazinamium iodide and thiazinamium sulfoxide iodide, 36 and 47%, respectively, of the administered dose were excreted in bile during 1 hr. TLC analysis of the bile showed at least two unidentified polar metabolites in addition to thiazinamium sulfoxide and only 3.8% unchanged thiazinamium after administration of thiazinamium iodide. The same metabolites were found after injection of thiazinamium sulfoxide iodide. Urinary excretion and intestinal secretion were 18 and 12%, respectively, for thiazinamium sulfoxide iodide and 27 and 9%, respectively, of the dose for thiazinamium iodide. It is concluded that, in spite of unequal physicochemical features, thiazinamium iodide and thiazinamium sulfoxide iodide differ only slightly in hepatic uptake and metabolism.

Animals↗

PubMed1979

Organic anion and cation transport in vitro by dog choroid plexus: effects of neuroleptics and tricyclic antidepressants.

Dog lateral choroid plexus accumulates the cation 14C-emepronium and the divalent anion 125I-iodipamide in vitro. At 10 micron, high potency neuroleptics with a substituted piperazine side chain and also haloperidol depress only the uptake of the cation and even stimulate the uptake of the anion. In contrast, at 1--10 micron, the accumulation of both test substances is inhibited by neuroleptics and tricyclic antidepressants with an aliphatic side chain. Such unspecific effects on seemingly unrelated transport systems at concentrations reached clinically in the CSF might explain some side actions of low potency neuroleptics and antidepressants.

Animals↗

PubMed1979

Organotin-mediated exchange diffusion of anions in human red cells.

Organotin cations (R3Sn+) form electrically neutral ion pairs with monovalent anions. It is demonstrated that the tin derivatives induce exchange diffusion of chloride in red cells and resealed ghosts, without any detectable increase of membrane permeability to net movements of chloride ions. The obligatory anion exchange is believed to be due to the permeation of electroneural ion pairs, whereas the organic cation (R3Sn+) has an extremely low membrane permeability. Exchange fluxes of chloride increased with the lipophilicity of the substituting group (R3). At the same molar concentration of organotin, the relative potencies of the tin derivatives as anion carriers (with trimethyltin as a reference) were: methyl 1, ethyl 30, propyl = phenyl 1,00, and butyl 10,000. Tributyltin-mediated anion exchange was studied in detail. The organotin-induced anion transport increased through the sequence: F- less than Cl- less than Br- less than I- = SCN- less than OH-. Partitioning of tributyltin into red cell membranes was greater in iodide than in chloride media (partition coefficients 6.6 and 1.7 x 10(-3) cm, respectively). Bicarbonate, fluoride, nitrate, phosphate, and sulphate did not exchange with chloride in the presence of tributyltin. Chloride exchange fluxes increased linearly with tributylin concentrations up to 10(-5) M, and with chloride concentrations up to at least 0.9 M. The apparent turnover number for tributyltin-mediated chloride exchange increased from 15 to 1,350 s-1 between 0 and 38 degrees C. These figures are minimum turnover numbers, because it is not known what fraction of the organotin in the membrane exists as chloride ion pairs.

Adsorption↗

PubMed1977

Secretion of monoquaternary ammonium compounds by guinea pig small intestine in vivo.

In anesthetized guinea pigs N-(3H)methylscopolamine (NMScop), N1-(14C)methylnicotinamide (NMN), and (14C)tetraethylammonium (TEA), administered intravenously, were secreted against a concentration gradient into the lumen of the small intestine. The concentration ratio of unmetabolized ammonium base in the intestinal lumen to that in the plasma was 4.3 and 6.5 for NMScop and NMN, respectively, 75 min after the intravenous injection of 1 nmole/g body weight of the individual compounds. The corresponding value for TEA after 180 min was 2.0. The establishment of the concentration gradient between intestinal lumen and plasma was diminished with increasing doses. An excess of NMN inhibited the uphill transport of NMScop. Since the electrical potential difference across the intestinal epithelium and a 'fluid circuit' mechanism cannot solely account for the observed accumulation of the monoquaternary ammonium compounds in the intestinal lumen, the evidence presented supports previous in vitro findings that the small intestine is capable of actively secreting organic cations.

Animals↗

PubMed1978

Effect of membrane cholesterol on potassium transport in Mycoplasma mycoides var. Capri (PG3).

Relationships between membrane lipid composition and physiological properties, particularly intracellular potassium levels, have been studied at 37 degrees C in Mycoplasma mycoides var. Capri (PG3). Native organisms grown on medium supplemented with either oleic acid plus palmitic acid or elaidic acid have identical growth characteristics, acidification properties and intracellular K content. On the other hand, when the cholesterol normally present in the membrane (20--25% of total lipids) is reduced to less than 2%, we observe: (1) the intracellular K content decreases (20 microgram K/mg cell protein instead of 40) and is independent of the phase of growth; (2) K passive permeability is drastically increased but K distribution remains in equilibrium with the transmembrane potential (delta psi); (3) organisms stop growing at pH 6.5 (instead of 5.2) and acidification is reduced by 40%, suggesting a large increase in H+ permeability, and (4) intracellular Na contents rise from 3 to 9 microgram Na/mg cell protein. Replenishing cholesterol in membranes of depleted cells results in a recovery of the high intracellular K level (35--40 microgram K/mg cell protein) and acidification properties. It is suggested that cholesterol affects the cation content via the increase in proton permeability which in turn controls the value of the delta psi responsible for the value of intracellular K equilibrium. Changes in K passive permeability, although related to the amount of cholesterol present in the plasma membrane, are probably not involved in the control of the intracellular K level.

Biological Transport↗

PubMed1978

Demonstration of diphtheria toxin receptors on surface membranes from both toxin-sensitive and toxin-resistant species.

A detailed binding study of 125I-labeled diphtheria toxin to isolated cell surface membrane-enriched fractions is reported. The study was undertaken to determine if toxin-resistant species exhibit a defet in either the binding step or the transport step of the intoxication process. Surface membrane fractions were obtained from liver and mammary glands of toxin-sensitive species, rabbit and giunea pig, and toxin-resistant species, rat mouse. All membrane fractions exhibited reversible binding of 125I-toxin which was competitively inhibited by unlabeled toxin. Toxin receptors from liver co-purified with plasma membranes and the plasma membrane marker 5'-nucleotidase. One-half saturation of all receptors occurred between 5 x 10(-8) and 1.8 x 10(-7) M. Scatchard plots were nonlinear and concave upwards. Total receptor sites ranged from 3.4 to 16 pmol/mg of membrane protein, tissue differences being more pronounced than difference between sensitive and nonsensitive species. Over 95% of the toxin specific binding was inhibited by removal of divalent cation from the medium or by the inclusion of 1 mM ATP, procedures which have been shown to protect sensitive cells from intoxication by diphtheria toxin. We conclude that the rat and mouse have surface membrane receptors for diphtheria toxin and that the toxin insensitivity of these species results from a defect in or a lack of the transport process.

Animals↗

PubMed1977

Oxidative response to aldosterone of pyridine nucleotide in rat kidney in situ.

In an attempt to elucidate early biochemical events in the action of aldosterone on rat kidney in situ, the response of the pyridine nucleotide oxidation-reduction state of surface cells was directly and continuously recorded with an organ-fluorometer. Intravenous administration of aldosterone induced a rapid (maximum response in 10 min) and dose-related (2.5-25 microng/100 g rat) oxidative response that was specific to aldosterone and to the kidney. The oxidative response was 1) detectable with minute dise (approximately 0.2 microng/100 g rat) of hormone: 2) reproduced by other mineralocorticoids; 3) enhanced by a maneuver for expanding the extracellular fluid compartment or by adrenalectomy; and 4) prevented by spironolactone, progesterone, actinomycin D, and cycloheximide. All of these data argue that the redox response is related to the subsequent changes in aldosteronemediated ion transport. Experiments with an uncoupler and with redox substrates showed that mitochondrial NADH was the major nucleotide pool responding to hormone. The oxidation was not accompanied by changes in the adenylate energy charge level of the whole organ. These observations support the view that aldosterone acts on energy metabolism of tubular cells before developing apparent cation transport effects.

Adenine Nucleotides↗

PubMed1978

Effects of various divalent cations on the survival of Neisseria gonorrhoeae in liquid media.

The effect of various concentrations of divalent cations on survival of gonococci in liquid medium was studied. The growth of Neisseria gonorrhoeae was inhibited by manganous chloride in concentrations above 1 X 10(-5)mol/l while the growth of control organisms such as Neisseria meningitidis and Escherichia coli was not inhibited by the same salt even at 1 X 10(-2)mol/l. Copper sulphate, cobaltous nitrate, nickel chloride, and zinc sulphate also had deleterious effects on gonococci. Magnesium chloride at 1.5 X 10(-1)mol/l permitted the growth of gonococci. The toxicity of manganous chloride and copper sulphate in the liquid media was in some measure reduced by adding charcoal but not by adding starch. The significance of these findings is discussed in relation to the efficiency of primary isolation and transport media for gonococci.

Cobalt↗

PubMed2024

SLC40A1-related hemochromatosis associated with a p.Y333H mutation in mainland China: a pedigree report and literature review.

BACKGROUND: Haemochromatosis is a genetic disease characterized by the excessive deposition of iron in various tissues and organs, eventually results in organ damage including cirrhosis, diabetes, cardiomyopathy, etc. SLC40A1-related haemochromatosis is associated with gain-of-function mutations in the SLC40A1 gene, which encodes ferroportin. While sporadic reports of this condition exist in mainland China, the understanding of the phenotype and genetic pattern associated with the SLC40A1 p.Y333H mutation remains incomplete. CASE PRESENTATION: We report a pedigree with heterozygous p.Y333H mutation in Chinese Han population. The proband is a 64-year-old man complaining of persistent abnormality of liver enzyme levels for 1 year, with a history of knee joint pain, diabetes and skin pigmentation. He displayed markedly elevated serum ferritin level and transferrin saturation. Magnetic resonance imaging showed iron deposition in the liver, spleen, and pancreas, along with cirrhosis and splenomegaly. Whole exome sequencing identified a heterozygous allelic variant c.997T > C (p.Y333H). Genetic screening of family members identified four first-degree relatives and three second-degree relatives having the same mutation. Additional cases with this mutation from two published studies were included. Among the probands and screened relatives, all eight males aged over 30 y had ferritin level > 1000 µg/L, transferrin saturation > 90%. Four patients with organ damage in the present study received therapeutic phlebotomy, alleviating clinical symptoms and improving in transferrin saturation and serum ferritin. CONCLUSIONS: This study reports the largest pedigree with heterozygous SLC40A1 p.Y333H mutation in the Chinese population to date. In Chinese families, males over 30 years old with hemochromatosis due to SLC40A1 p.Y333H mutation exhibit severe iron overload phenotypes.

Humans↗

PubMed1978

Human serum histidine-rich glycoprotein. I. Interactions with heme, metal ions and organic ligands.

The 3.8 S alpha2-histidine-rich glycoprotein of human serum is composed of two non-identical subunits, each of which contains carbohydrate. The far ultraviolet circular dichroism spectrum of alpha2-histidine glycoprotein indicates that the protein has little alpha-helix but apparently appreciable amounts of beta-sheet and non-regular structures. alpha2-Histidine-rich glycoprotein binds heme with concomitant changes in the electrophoretic mobility of the protein, in the fluorescence of tryptophan residues, and in the absorption and optical activity of the heme chromophore. By fluorescence quenching, the stoichiometry of binding is 1 heme per alpha2-histidine-rich glycoprotein molecule with an apparent Kd near 1.5 muM; however, by changes in absorbance, the interaction of 9 to 10 additional heme molecules with the alpha protein can be detected. The absorption spectra of heme . alpha2-histidine-rich glycoprotein complexes resemble those of low-spin hemoproteins. The ellipticity induced in the heme chromophore on binding by alpha2-histidine-rich glycoprotein increases linearly up to about 10 hemes bound per mol protein. No change in the conformation of alpha2-histidine-rich glycoprotein was indicated by circular dichroism when one or two heme molecules are bound by the protein. alpha2-Histidine-rich glycoprotein does not effectively compete with human serum albumin for heme, suggesting that alpha2-histidine-rich glycoprotein has no major function in serum heme transport. Nonetheless, the binding of heme by alpha2-histidine-rich glycoprotein provides a means of studying the structure of this protein using the heme chromophore as a probe. alpha2-Histidine-rich glycoprotein also binds other organic molecules including bilirubin, diaquocobinamide, Cibacron blue F3GA and rose bengal, and certain divalent metals. It is of interest that copper, zinc, nickel, cadmium and cobalt effectively inhibit the binding of heme by alpha2-histidine-rich glycoprotein, whereas other divalent metals tested, including calcium, magnesium and manganese do not appreciably affect the heme-alpha2-histidine-rich glycoprotein interaction.

Amino Acids↗

PubMed2004

Function-informed transcriptome analysis of Drosophila renal tubule.

BACKGROUND: Comprehensive, tissue-specific, microarray analysis is a potent tool for the identification of tightly defined expression patterns that might be missed in whole-organism scans. We applied such an analysis to Drosophila melanogaster Malpighian (renal) tubule, a defined differentiated tissue. RESULTS: The transcriptome of the D. melanogaster Malpighian tubule is highly reproducible and significantly different from that obtained from whole-organism arrays. More than 200 genes are more than 10-fold enriched and over 1,000 are significantly enriched. Of the top 200 genes, only 18 have previously been named, and only 45% have even estimates of function. In addition, 30 transcription factors, not previously implicated in tubule development, are shown to be enriched in adult tubule, and their expression patterns respect precisely the domains and cell types previously identified by enhancer trapping. Of Drosophila genes with close human disease homologs, 50 are enriched threefold or more, and eight enriched 10-fold or more, in tubule. Intriguingly, several of these diseases have human renal phenotypes, implying close conservation of renal function across 400 million years of divergent evolution. CONCLUSIONS: From those genes that are identifiable, a radically new view of the function of the tubule, emphasizing solute transport rather than fluid secretion, can be obtained. The results illustrate the phenotype gap: historically, the effort expended on a model organism has tended to concentrate on a relatively small set of processes, rather than on the spread of genes in the genome.

Animals↗