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PubMed2003

[Molecular characteristics and tissue distribution of peptide transporters].

At present, there are at least five kinds of peptide transporters identified in animal tissues, in which PepT1 and PepT2 were discussed most extensively. PepT1 and PepT2 are all members of proton-dependent oligopeptide transporters(POT) family. PepT1 is peptide transporter of low affinity and high capacity whereas PepT2 is high affinity and low capacity. PepT1 is mainly expressed in intestinal tract and weakly expressed in kidney, but PepT2 is mainly expressed in kidney. These transporters have some significant molecular characteristics: (1) Contain 12 membrane-spanning domains and a large extracellular loop between transmembrane domains 9 and 10, and all of the transmembrane domains are highly conserved, the extracellular loops are much less so; (2) The encoded proteins have a number of potential N-glycosylation as well as protein kinase recognition sites, which may be involved in the regulation of peptide transport; (3) His-57 in PepT1 and His-87 in PepT2 are the most critical histidyl residues that are necessary for the uptake function and probably represent some critical binding sites; (4) The proteins range in size from 707 to 729 amino acid residues in various species, with higher homology between species for a given transporter (approximately 80%) and less homology between transporters for a given species (approximately 50%). With the knowledge of the molecular characteristics and tissue distribution of these peptide transporters, we can understand the molecular mechanism underlying the peptide absorption, which may improve the peptide-drugs development in the future.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

The pharmacokinetics and tissue distribution of sinomenine in rats and its protein binding ability in vitro.

Sinomenine, an alkaloid derived from the Chinese medical plant Sinomenium acutum, was studied with regard to its pharmacokinetics and tissue distribution in rats, and to its protein binding ability in the plasma of rats and rabbits and in the solutions of albumin and alpha-1-acid-glycoprotein. An HPLC analytical method was developed for determining sinomenine. The results demonstrated that oral administration with a single dosage at a rate of 90 mg sinomenine/kg in rats achieved about 80% bioavailability, while most of the other pharmacokinetic parameters were similar to the data from the animals treated intravenously. This indicates that oral administration of sinomenine would be appropriate in clinics. In rats, at 45 min after oral dosage, the drug was found to distribute widely in the internal organs, with tissue concentrations (from highest to lowest) in the order of kidneys, liver, lungs, spleen and heart, brain and testicles. At 90 min after dosing, the tissue concentrations in the organs were markedly decreased. The liver and kidneys manifested as the dominant organs with high tissue concentrations that might be responsible for metabolism and elimination of sinomenine. Examination of the protein binding ability showed that sinomenine with 4 microg/ml concentration in the plasma of rats and rabbits or in the albumin solution achieved a protein binding rate of more than 60%, while in the solution of alpha-1-acid-glycoprotein the rate was only about 33%. This result suggests that sinomenine might have much more potent binding ability with albumin than with alpha-1-acid-glycoprotein, resulting from its acidic property.

Administration, Oral↗

PubMed1991

The tissue distribution of 2,3,7,8-chlorine substituted dibenzo-p-dioxins in humans who died of cancer.

The tissue distribution of 2,3,7,8-chlorine substituted dibenzo-p-dioxins was conducted in 11 patients who died of cancer. The concentration of octachlorodibenzo-p-dioxin (octa-CDD) was the highest in each organ and tissue and hepta-CDD was also found at relatively high levels, second only to OCDD. The levels of 1,2,3, 7,8-penta-CDD and 1,2,3,6,7,8-hexa-CDD in the spleen were the highest, respectively. 2,3,7,8-Tetra-CDD was also detected and its concentration was the highest in the gonad (0.8-3.2 pg/g-range). From the 2,3,7,8-TCDD toxic equivalent calculations, the highest equivalent value was obtained from a 54-year-old female who died of cancerous goiter. This individual had the highest concentrations of 2,3,7,8-substituted penta- and hexa-CDDs among the 11 patients.

Aged↗

PubMed1999

Tissue distribution of rat macroglobulins in tumour-bearing rats.

Rat macroglobulins were determined in blood sera and extracts of tissues of intact rats and rats with Walker carcinoma by rocket immunoelectrophoresis. The serum levels of alpha1-macroglobulin (alpha1MG) alpha2-macroglobulin (alpha2MG) and pregnancy-associated alpha1-glycoprotein (alpha1PAG) were 1.86 +/- 0.07 mg/ml, 0.12 +/- 0. 02 mg/ml and 18.32 +/- 4.07 AU/ml respectively in control rats. Maximum concentrations of alpha1MG were found in heart, lung and spleen and lesser quantities were in liver and thymus, while alpha2MG and alpha1PAG were not found at all in tissue extracts from control rats. Serum alpha2MG and alpha1PAG concentrations increased more than 30-fold in tumour-bearing rats compared to control animals, while alpha1MG serum concentration was little changed. Increases in all three macroglobulins occurred in the tissues of tumour-bearing rats, particularly alpha1PAG. The tissue concentrations of alpha1MG and alpha2MG were similar and the tissue distribution was also similar with highest concentrations in heart and lung. Considerable quantities of the proteins were found in the tumour and part of peritoneum which made contact with the tumour. Changes in the protein concentrations in serum and tissue extracts of tumour-bearing rats suggest that all members of rat macroglobulin family are disturbed during the development of the Walker carcinoma, though only alpha2MG and alpha1PAG were substantially elevated.

Animals↗

PubMed1984

Tumor and tissue distribution of a methotrexate-anti-EL4 immunoglobulin conjugate in EL4 lymphoma-bearing mice.

The uptake and tissue distribution of [3H]methotrexate [( 3H]MTX) at doses of 5 mg/kg i.p. either free or linked to anti-EL4 immunoglobulin G (AELG) or normal rabbit globulin (NRG) was studied in EL4 lymphoma-bearing C57BL/6J mice. When the uptakes of MTX-AELG, MTX-NRG, and free MTX were assayed as cell-associated 3H activity, comparison 3 hr after administration showed that uptake of MTX administered as the AELG conjugate was 2.5 times the uptake of MTX administered as the NRG conjugate and 6 times the uptake of MTX administered free. In contrast to the difference in the uptake of MTX-AELG and MTX-NRG by tumor cells, the pattern of uptake in all the other tissues studied was generally similar for the two conjugates. Conjugated MTX persisted in all tissues and serum and ascites fluid, whereas free MTX declined rapidly after reaching peak levels around 1 hr, except in EL4 cells where 45% was retained at 24 hr. The levels of intracellular MTX after administration of these three agents exceeded the intracellular dihydrofolate reductase level and correlated with the relative tumor-inhibitory effect in vivo of the agent (MTX-AELG greater than MTX-NRG greater than MTX).

Animals↗

PubMed1980

Elimination pattern and tissue distribution of intravenous iron-poly (sorbitol-gluconic acid) complex in the rat.

The elimination pattern and tissue distribution in rats of intravenous [14C-gluconic acid]-poly(sorbitol-gluconic acid) and 59Fe-iron-poly(sorbitol-gluconic acid) complex, glusoferron (Ferastral) have been examined. Twenty-four hours after injection of 20 or 200 mg/kg of [14C-gluconic acid]-poly(sorbitol-gluconic acid), 5%-6% of the injected dose of radiolabel was eliminated as 14CO2 and about 85% in the urine and faeces. Administration of 59Fe-iron-poly(sorbitol-gluconic acid) complex (10 and 100 mg of iron/kg) resulted in a urinary and faecal excretion of about 18% and 40% of the given dose, respectively, during the first 4 days. Biliary excretion was low. The mean molecular weight of the biliary product after the iron complex was lower than that of the parent compound. Radiocarbon in tissues after 24 hours was negligible. Liver and bones accounted for most of the retained radioiron following 100 mg of iron/kg bodyweight of the 59Fe-iron complex with maximum levels of 27% and 12% of the injected dose, respectively, 4 days after dosing. Red cell incorporation of 59Fe attained a level of 16% at the end of 28 days.

Animals↗

PubMed1984

Tissue distribution of poly(hexyl 2-cyanoacrylate) nanoparticles coated with monoclonal antibodies in mice bearing human tumor xenografts.

The tissue distribution of naked and either normal immunoglobulin G or monoclonal antibody (antitumor osteogenic sarcoma)-coated poly(hexyl-2-cyanoacrylate) nanoparticles was studied in mice bearing human tumor xenografts to evaluate the applicability of the systems for tumor targeting. All systems were shown to deposit mainly in the liver and spleen and no significant uptake was found in the tumors for either the naked or antibody-coated nanoparticles.

Adsorption↗

PubMed1999

Plasmid DNA malaria vaccine: tissue distribution and safety studies in mice and rabbits.

To evaluate the safety of a plasmid DNA vaccine, tissue distribution studies in mice and safety studies in mice and rabbits were conducted with VCL-2510, a plasmid DNA encoding the gene for the malaria circumsporozoite protein from Plasmodium falciparum (PfCSP). After intramuscular administration, VCL-2510 plasmid DNA was detected initially in all of the highly vascularized tissues, but at later time points was found primarily in the muscle at the site of injection, where it persisted for up to 8 weeks. After intravenous administration, plasmid DNA initially distributed at a relatively low frequency to all the tissues examined except the gonads and brain. However, plasmid DNA rapidly cleared, and by 4 weeks postadministration could be detected only in the lung of one of six animals evaluated. In a safety study in mice, eight repeated intramuscular injections of VCL-2510 at plasmid DNA doses of 1, 10, and 100 microg had no adverse effects on clinical chemistry or hematology, and did not result in any organ pathology or systemic toxicity. In a safety study in rabbits, six repeated intramuscular injections of VCL-2510 at plasmid DNA doses of 0.15 and 0.45 mg had no discernible effects on clinical chemistry, hematology, or histopathology. No evidence of autoimmune-mediated pathology, anti-nuclear antibodies (ANA), or antibodies to dsDNA were observed in the mouse or rabbit studies.

Age Factors↗

PubMed1986

Disposition of metals in rats: a comparative study of fecal, urinary, and biliary excretion and tissue distribution of eighteen metals.

Fecal (0-4 days), urinary (0-4 days), and biliary (0-2 hr) excretion and tissue distribution of 18 metals were examined in rats after iv administration. Total (fecal + urinary) excretion was relatively rapid (over 50% of dose in 4 days) for cobalt, silver, and manganese; was between 50 and 20% for copper, thallium, bismuth, lead, cesium, gold, zinc, mercury, selenium, and chromium; and was below 20% for arsenic, cadmium, iron methyl mercury, and tin. Feces was the predominant route of excretion for silver, manganese, copper, thallium, lead, zinc, cadmium, iron, and methyl mercury whereas urine was the predominant route of excretion for cobalt, cesium, gold, selenium, and chromium; while both excretion routes were equally important for bismuth, mercury, arsenic, and tin. Biliary excretion seems to be an important determinant for the fecal excretion of silver, arsenic, manganese, copper, selenium, cadmium, lead, bismuth, cobalt, and methyl mercury. Between 45 (silver) and 0.8% (methyl mercury) of the dosages administered of these metals was excreted into bile in 2 hr, and they exhibited high bile/plasma concentration ratios. The biliary excretion of copper, selenium, lead, and chromium did not increase proportionally with dosage, suggesting that the hepatobiliary transport of these metals is saturable. The fraction of dosage excreted into bile was independent of the dosage for silver, arsenic, manganese, bismuth, methyl mercury, mercury, gold, cesium, thallium, and tin, but markedly increased with increase in dosage of cadmium, cobalt, zinc, and iron. The latter phenomenon is probably due to saturation of hepatic (cadmium, zinc) or extrahepatic (iron) metal-binding sites. Comparison of biliary and fecal excretion rates indicates that arsenic and selenium undergo intestinal reabsorption, whereas thallium and zinc enter the feces also by non-biliary routes. Most of the metals reached the highest concentration in liver and kidney. However, there was no direct relationship between the distribution of metals to these excretory organs and their primary route of excretion.

Animals↗

PubMed1995

Tissue distribution of fusion regulatory protein-1 and fusion regulatory protein-2.

OBJECTIVE: To show which organs (tissues or cells) express fusion regulatory protein-1 and -2. DESIGN: Tissue distribution of fusion regulatory protein-1 and -2 was investigated by indirect immunofluorescence and indirect immunoperoxidase techniques on cryostat tissue sections, using anti-fusion regulatory protein-1 and -2 monoclonal antibodies. RESULTS: Immunohistochemical analysis of human tissue sections revealed the expression of fusion regulatory protein-1 on hair follicle epithelium, skeletal muscle sarcolemma, some bone marrow stem cells, stomach surface and glandular epithelia, pancreatic islets, kidney proximal tubules, testicular seminiferous tubules, follicular epithelium and ova in the ovary, and parathyroid gland. Fusion regulatory protein-2 was expressed on kidney glomerular basement membrane and many glandular epithelia, such as the skin, stomach, thyroid gland, and lung. CONCLUSIONS: The distribution suggested that the expression of fusion regulatory protein-1 might be related to proliferation, peptide or protein secretion, and cell fusion. The distribution of fusion regulatory protein-2 was identical to that of the alpha 3 subunit of integrin.

Antigens, Surface↗

PubMed2001

Cloning, characterization, and tissue distribution of prolactin receptor in the sea bream (Sparus aurata).

The prolactin receptor (PRLR) was cloned and its tissue distribution characterized in adults of the protandrous hermaphrodite marine teleost, the sea bream (Sparus aurata). An homologous cDNA probe for sea bream PRLR (sbPRLR) was obtained by RT-PCR using gill mRNA. This probe was used to screen intestine and kidney cDNA libraries from which two overlapping clones (1100 and 2425 bp, respectively) were obtained. These clones had 100% sequence identity in the overlapping region (893 bp) and were used to deduce the complete amino acid sequence of sbPRLR. The receptor spans 2640 bp and encodes a protein of 537 amino acids. Features characteristic of PRLR, two pairs of cysteines, WS box, hydrophobic transmembrane domain, box 1, and box 2, were identified and showed a high degree of sequence identity to PRLRs from other vertebrate species. SbPRLR is 29 and 32% identical to tilapia (Oreochromis niloticus) and goldfish (Carassius auratus) PRLRs, respectively. In the sea bream two PRLR transcripts of 2.8 and 3.2 kb were detected in the intestine, kidney, and gills and a single transcript of 2.8 kb was detected in skin and pituitary by Northern blot. Spermiating gonads (more than 95% male tissue; gonado-somatic index of 0.6) contained, in addition to the 2.8-kb transcript, three more transcripts of 1.9, 1.3, and 1.1 kb. RT-PCR, which is a far more sensitive method than Northern blot, detected PRLR mRNA in gills, intestine, brain, pituitary, kidney, liver, gonads, spleen, head-kidney, heart, muscle, and bone. Immunohistochemistry using specific polyclonal antibodies raised against an oligopeptide from the extracellular domain of sbPRLR detected PRLR in several epithelial tissues of juvenile sea bream, including the anterior gut, renal tubule, choroid membrane of the third ventricle, saccus vasculosus, branchial chloride cells, and branchial cartilage.

Amino Acid Sequence↗

PubMed1987

Cloning and tissue distribution of rat heart fatty acid binding protein mRNA: identical forms in heart and skeletal muscle.

A fatty acid binding protein (FABP) has been identified and characterized in rat heart, but the function and regulation of this protein are unclear. In this study the cDNA for rat heart FABP was cloned from a lambda gt11 library. Sequencing of the cDNA showed an open reading frame coding for a protein with 133 amino acids and a calculated size of 14776 daltons. Several differences were found between the sequence determined from the cDNA and that reported previously by protein sequencing techniques. Northern blot analysis using rat heart FABP cDNA as a probe established the presence of an abundant mRNA in rat heart about 0.85 kilobases in length. This mRNA was detected, but was not abundant, in fetal heart tissue. Tissue distribution studies showed a similar mRNA species in red, but not white, skeletal muscle. In general, the mRNA tissue distribution was similar to that of the protein detected by Western immunoblot analysis, suggesting that heart FABP expression may be regulated at the transcriptional level. S1 nuclease mapping studies confirmed that the mRNA hybridized to rat heart FABP cDNA was identical in heart and red skeletal muscle throughout the entire open reading frame. The structural differences between heart FABP and other members of this multigene family may be related to the functional requirements of oxidative muscle for fatty acids as a fuel source.

Amino Acid Sequence↗

PubMed1995

Body compartment and subcutaneous adipose tissue distribution--risk factor patterns in obese subjects.

The purpose of this study was to investigate whether upper body obesity and/or visceral obesity are related to cardiovascular risk factors among severely obese subjects, phenomena that have previously been reported in more heterogeneous body weight distributions. 2450 severely obese men and women aged 37 to 59 years, with a body mass index of 39 +/- 4.5 kg/m2 (mean +/- SD) were examined cross-sectionally. Eight cardiovascular risk factors were studied in relation to the following body composition indicators: four trunk and three limb circumferences, along with weight, height and sagittal trunk diameter. From the latter three measurements lean body mass (LBM, i.e., the non-adipose tissue mass) and the masses of subcutaneous and visceral adipose tissue were estimated by using sex-specific prediction equations previously calibrated by computed tomography. Two risk factor patterns could be distinguished: 1. One body compartment-risk factor pattern in which the subcutaneous adipose tissue (AT) mass and, in particular, the visceral AT mass were positively related to most risk factors while the lean body mass was negatively related to some risk factors. 2. One subcutaneous adipose tissue distribution- risk factor pattern in which the neck circumference was positively and the thigh circumference negatively related to several risk factors. It is concluded that lean body mass (LBM), visceral and subcutaneous adipose tissue masses as well as neck and thigh circumferences, used as indices of subcutaneous adipose tissue distribution, are independently related to cardiovascular risk factors in severely obese men and women.

Adipose Tissue↗

PubMed1994

Tissue distribution of polybutylcyanoacrylate nanoparticles loaded with spin-labelled nitrosourea in Lewis lung carcinoma-bearing mice.

The tissue distribution of polybutylcyanoacrylate nanoparticles (PBCN) with a diameter of 127 nm, loaded with 1-(2-chloroethyl)-3-(1-oxyl-2,2,6,6-tetramethylpiperidinyl)-1- nitrosourea (spin-labelled nitrosourea, SLCNU) is described. PBCN-suspensions were intraperitoneally (i.p.) injected into Lewis lung carcinoma bearing mice. The biodistribution of PBCN in the visceral organs, blood and tumor was studied by electron spin resonance (ESR) spectroscopy. A relatively low accumulation of nanoparticles in the liver and spleen was found. The accumulation was negligible in the i.m. implanted primary tumor. SLCNU-loaded nanoparticles were mainly found in the lungs, kidneys, and heart. The highest content of the particles studied was observed in the lungs of tumor bearing experimental animals damaged by metastases. These findings suggest that PBCN offer some opportunities in the targeting of SLCNU to lung metastases.

Animals↗

PubMed1983

A tissue distribution model for assessment of human inhalation exposures to 241AmO2.

A model useful for predicting lung retention and tissue distribution following human inhalation exposure to 241AmO2 has been formulated. The model is based on inhalation studies in beagles exposed to either monodisperse or polydisperse aerosols of 241AmO2. It also describes lung retention for several cases of accidental human inhalation exposure to 241Am adequately. The model incorporates an expression for solubilization of 241AmO2 deposited in lung which is based on physicochemical characteristics of the inhaled particles. Comparison of predictions from this model and those of the International Commission of Radiological Protection in ICRP Publication 30 shows some important differences. Lung retention patterns of inhaled 241Am in dogs and humans after inhalation of 241AmO2 are very similar and do not conform with predictions of the ICRP 30 model. Although use of the ICRP 30 model for calculation of annual limits of intake produces similar values to predictions made from our model, a more complete assessment of accidental human exposures to 241AmO2 and the risk to individual organs can be made using the retention and dosimetry model formulated from these studies in dogs.

Americium↗

PubMed1993

Tissue distribution of autoantigen specific for primary sclerosing cholangitis.

AIM: To investigate the tissue distribution of the autoantigen specific for primary sclerosing cholangitis. METHODS: A range of normal frozen tissues including nervous system, muscle, uterus, ovary, prostate, pancreas, thyroid, salivary gland, adrenal gland, colon, gall bladder, stomach, jejunum, aorta, skin, kidney, liver, spleen and thymus was sectioned, fixed with acetone, and air-dried. Normal bone marrow and HL60, K562, and U937 cells were cytocentrifuged on to slides, air-dried, and alcohol fixed. Four sera from primary sclerosing cholangitis with high titre antibody (> 1/100) were used to screen the tissues using either two-step or APAAP immunohistochemistry. Normal sera were used as controls. RESULTS: Positive signal was detected in neutrophils in spleen with three out of four primary sclerosing cholangitis sera while one out of four primary sclerosing cholangitis sera stained spindle cells in the liver. All four sera stained mature neutrophils of the normal bone marrow. Some bone marrow neutrophil precursors (metamyelocytes and myelocytes) were also positive. All other tissues, including HL60, K562, and U937 cells, were negative. Normal sera were negative on all tissues. CONCLUSION: Antigen specific for primary sclerosing cholangitis seems to be unique to neutrophil polymorphs and is present only after myeloblast differentiation of the myeloid cell line. The antigen may be within the secondary granule of the neutrophil polymorph.

Adult↗

PubMed2003

Intraocular tissue distribution of betamethasone after intrascleral administration using a non-biodegradable sustained drug delivery device.

PURPOSE: To evaluate the tissue distribution of betamethasone (BM) after implantation of a nonbiodegradable intrascleral implant as a new, controlled intraocular delivery system. METHODS: Nonbiodegradable intrascleral implants designed to release BM for at least 1 month were placed in the sclera of pigmented rabbits. The BM concentrations in the aqueous humor, vitreous, and retina-choroid were determined by high-performance liquid chromatography (HPLC) at 3, 7, 14, and 28 days after implantation. The BM concentrations in three sections of retina-choroid were also investigated. Retinal toxicity was evaluated by electroretinography and histology. RESULT: The BM released from the intrascleral implant in vitro and in vivo showed zero-ordered release profiles for 4 weeks. The BM concentrations in the retina-choroid after placement of the intrascleral implants remained higher than effective concentrations for suppressing various inflammatory processes for at least 28 days. The BM concentrations in the retina-choroid around the implantation site were more than 10 times higher than in the opposite side throughout the study. No substantial toxic reactions were observed by electroretinography or histology. CONCLUSIONS: These findings suggested that the nonbiodegradable intrascleral implant could be a useful drug carrier for intraocular delivery of BM without producing severe retinal toxicity. The intrascleral site may be considered for effective intraocular drug distribution after implantation.

Animals↗

PubMed1996

Structure, tissue distribution and genomic organization of the murine RRM-type RNA binding proteins TIA-1 and TIAR.

TIA-1 and TIAR are RNA binding proteins of the RNA recognition motif (RRM)/ribonucleoprotein (RNP) family that have been implicated as effectors of apoptotic cell death. We report the structures of murine TIA-1 and TIAR (mTIA-1 and mTIAR) deduced from cDNA cloning, the mRNA and protein tissue distribution of mTIA-1 and mTIAR, and the exon-intron structures of the mTIA-1 and mTIAR genes. Both mTIA-1 and mTIAR are comprised of three approximately 100 amino acid N-terminal RRM domains and a approximately 90 amino acid C-terminal auxiliary domain. This subfamily of RRM proteins is evolutionarily well conserved; mTIA-1 and mTIAR are 80% similar to each other, and 96 and 99% similar to hTIA-1 and hTIAR, respectively. The overall exon-intron structures of the mTIA-1 and mTIAR genes are also similar to each other, as well as to the human TIA-1 gene structure. While Northern blot analysis reveals that mTIA-1 and mTIAR mRNAs have a broad tissue distribution, mTIA-1 and mTIAR proteins are predominantly expressed in brain, testis and spleen. At least two isoforms of both mTIA-1 and mTIAR are generated by alternative splicing. Murine TIA-1 isoforms including or lacking the exon 5 encoded sequences are expressed at a ratio of approximately 1:1, whereas mTIAR isoforms including or lacking the 5'-end of exon 3 sequences are expressed in a approximately 1:6 ratio. Molecular characterization of murine TIA-1 and TIAR RNA binding proteins provides the basis for a genetic analysis of the functional roles of these proteins during mammalian development.

Amino Acid Sequence↗