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The compound N -(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), which combines a selenium atom and a benzamide nucleus in an organic structure, has demonstrated a fast antidepressant-like effect in mice. This action is influenced by the serotonergic system and represents a promising development in the search for novel antidepressant drugs to treat major depressive disorder (MDD), which often resists conventional treatments. This study aimed to further explore the mechanism underlying the antidepressant-like effect of SePB by investigating the involvement of the dopaminergic and noradrenergic systems in the tail suspension test (TST) in mice and evaluating its pharmacokinetic profile in silico. Preadministration of the dopaminergic antagonists haloperidol (0.05 mg/kg, intraperitoneally (i.p.)), a nonselective antagonist of dopamine (DA) receptors, SCH23390 (0.01 mg/kg, subcutaneously (s.c.)), a D 1 receptor antagonist, and sulpiride (50 mg/kg, i.p.), a D 2/3 receptor antagonist, before SePB (10 mg/kg, intragastrically (i.g.)) prevented the anti-immobility effect of SePB in the TST, demonstrating that these receptors are involved in the antidepressant-like effect of SePB. Administration of the noradrenergic antagonists prazosin (1 mg/kg, i.p.), an α 1 -adrenergic antagonist, yohimbine (1 mg/kg, i.p.), an α 2 -adrenergic antagonist, and propranolol (2 mg/kg, i.p.), a β-adrenergic antagonist, did not block the antidepressant-like effect of SePB on TST, indicating that noradrenergic receptors are not involved in this effect. Additionally, the coadministration of SePB and bupropion (a noradrenaline/dopamine reuptake inhibitor) at subeffective doses (0.1 and 3 mg/kg, respectively) produced antidepressant-like effects. SePB also demonstrated good oral bioavailability and low toxicity in computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses. These findings suggest that SePB has potential as a new antidepressant drug candidate with a particular focus on the dopaminergic system.

The review presents the latest data on the role of selenium-containing agents in the regulation of diseases of the immune system. We mainly considered the contributions of selenium-containing compounds such as sodium selenite, methylseleninic acid, selenomethionine, and methylselenocysteine, as well as selenoproteins and selenium nanoparticles in the regulation of defense mechanisms against various viral infections, including coronavirus infection (COVID-19). A complete description of the available data for each of the above selenium compounds and the mechanisms underlying the regulation of immune processes with the active participation of these selenium agents, as well as their therapeutic and pharmacological potential, is presented. The main purpose of this review is to systematize the available information, supplemented by data obtained in our laboratory, on the important role of selenium compounds in all of these processes. In addition, the presented information makes it possible to understand the key differences in the mechanisms of action of these compounds, depending on their chemical and physical properties, which is important for obtaining a holistic picture and prospects for creating drugs based on them.

The naturally occurring selenoneine (SeN), the selenium analogue of the sulfur-containing antioxidant ergothioneine, can be found in high abundance in several marine fish species. However, data on biological properties of SeN and its relevance for human health are still scarce. This study aims to investigate the transfer and presystemic metabolism of SeN in a well-established in vitro model of the blood-brain barrier (BBB). Therefore, SeN and the reference Se species selenite and Se-methylselenocysteine (MeSeCys) were applied to primary porcine brain capillary endothelial cells (PBCECs). Se content of culture media and cell lysates was measured via ICP-MS/MS. Speciation analysis was conducted by HPLC-ICP-MS. Barrier integrity was shown to be unaffected during transfer experiments. SeN demonstrated the lowest transfer rates and permeability coefficient (6.7 × 10-7 cm s-1) in comparison to selenite and MeSeCys. No side-directed accumulation was observed after both-sided application of SeN. However, concentration-dependent transfer of SeN indicated possible presence of transporters on both sides of the barrier. Speciation analysis demonstrated no methylation of SeN by the PBCECs. Several derivatives of SeN detected in the media of the BBB model were also found in cell-free media containing SeN and hence not considered to be true metabolites of the PBCECs. In concluding, SeN is likely to have a slow transfer rate to the brain and not being metabolized by the brain endothelial cells. Since this study demonstrates that SeN may reach the brain tissue, further studies are needed to investigate possible health-promoting effects of SeN in humans., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hericium erinaceus is a traditional edible mushroom. Selenium (Se) is an essential trace element for humans and other mammals. To develop a Se biofortification strategy for H. erinaceus, the effects of selenate, selenite, and selenomethionine (SeMet) on Se uptake and mushroom growth were investigated. Selenium bioaccessibility and the major Se species present in Se-enriched H. erinaceus were tested in vitro . The H. erinaceus growth was efficiently affected by SeMet than by selenite and selenate. Selenium concentrations in fruiting bodies increased with substrate Se concentration and disturbed accumulation of other microelements. Substrate Se was absorbed and transformed into organic forms. The major Se species in Se-enriched fruiting bodies was SeMet (>63.9%). During in vitro gastrointestinal digestion tests, 51% of total Se was released, and selenocystine (SeCys 2 ) (90%) and Se-methylselenocysteine (MeSeCys) (76%) were more easily digested than SeMet (51%). H. erinaceus is suggested as a novel dietary source of supplemental bioavailable Se., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Selenocompounds (SeCs) are promising therapeutic agents for a wide range of diseases including cancer. The treatment results are heterogeneous and dependent on both the chemical species and the concentration of SeCs. Moreover, the mechanisms of action are poorly revealed, which most probably is due to the detection methods where the quantification is based on the total selenium as an element. To understand the mechanisms underlying the heterogeneous cytotoxicity of SeCs and to determine their pharmacokinetics, we investigated selenium speciation of six SeCs representing different categories using liquid chromatography-mass spectrometry (LC-MS) and X-ray absorption spectroscopy (XAS) and the cytotoxicity using leukemic cells. SeCs cytotoxicity was correlated with albumin binding degree as revealed by LC-MS and XAS. Further analysis corroborated the covalent binding between selenol intermediates of SeCs and albumin thiols. On basis of the Se-S model, pharmacokinetic properties of four SeCs were for the first time profiled. In summary, we have shown that cytotoxic SeCs could spontaneously transform into selenol intermediates that immediately react with albumin thiols through Se-S bond. The heterogeneous albumin binding degree may predict the variability in cytotoxicity. The present knowledge will also guide further kinetic and mechanistic investigations in both experimental and clinical settings.

The synthesis of SCF 3 as well as SeCF 3 isosteres of two OCF 3 -containing drugs was achieved through visible light and copper-catalyzed processes. Herein, we show that chalcogen replacement modulates physicochemical and ADME properties without introducing intrinsic liabilities. The SCF 3 and SeCF 3 groups are more lipophilic than their oxygen counterpart; however, microsomal stability is unchanged, indicating that these molecular changes may be beneficial for in vivo half-life. Enabled by modern synthetic methods, we present the chalcogen-CF 3 groups as potential key players for future fluorinated pharmaceuticals., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Nunavimmiut (Inuit of Nunavik, Northern Quebec, Canada) exhibit a high selenium (Se) status because of their frequent consumption of marine mammal foods. Indirect evidence from our previous studies had suggested that selenoneine - a novel selenocompound - may be accumulating in the blood of Nunavimmiut. We used a liquid-chromatography/inductively coupled tandem mass spectrometry (LC-ICP-MS/MS) method to measure concentrations of selenoneine and its methylated metabolite Se-methylselenoneine in archived red blood cells (RBC) obtained from 210 Nunavimmiut living in communities along the Hudson Strait, where marine mammal hunting and consumption are most frequent in Nunavik. This method was adapted to quantify selenoneine and its methylated metabolite in beluga mattaaq, an Inuit delicacy consisting of the skin with the underlying layer of fat and the major dietary source of Se for Nunavimmiut. Total selenium concentration was also measured in RBC and beluga mattaaq samples by isotope dilution ICP-MS/MS. The median selenoneine concentration in RBC was 413 μg Se/L (range = 3.20-3230 μg Se/L), representing 54% (median) of total Se content (range = 1.6-91%). Quantification of selenoneine in five beluga mattaaq samples (skin layer) from Nunavik revealed a median concentration of 1.8 μg Se/g wet wt (range = 1.2-7.4 μg Se/g), constituting 54% (median) of the total Se content (range = 44-74%). Se-methylselenoneine was also detected in Inuit RBC but not in beluga mattaaq, suggesting that selenoneine undergoes methylation in humans. Selenoneine may protect Nunavimmiut from methylmecury toxicity by increasing its demethylation in RBC and in turn decreasing its distribution to target organs., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The lipopolysaccharide (LPS) is an endotoxin derived from gram-negative bacteria, which induces inflammation. The aims of this study were to evaluate the possible α-(phenylselanyl) acetophenone (PSAP) activity in reducing comorbid hyperalgesia, depressive-like and anxiogenic-like symptoms induced by LPS in mice. In additional, investigated physical chemical properties of PSAP through in silico analysis by ADMET predictor software. The LPS (100 μg/kg, intraperitoneally) or saline were administered and after 4 h the treatment with PSAP (0.001-10 mg/kg, intragastric route [i.g.]) or FLX (10 mg/kg, i.g.) was performed, and after 30 min, the behavioral tests were carried out. LPS reduced the latency time for the first episode of immobility and increased the immobility time in the FST as well as decreased the grooming time in the splash test. PSAP reversed these alterations demonstrating an antidepressive-like effect. LPS also enhances the anxiogenic behavior in the elevated plus maze test (EPM). PSAP reversed these parameters, showing anxiolytic-like effect. LPS also decreased the latency time (s) on the hot plate and the treatment with PSAP at all doses significantly reversed the hyperalgesic effect of LPS. LPS increased the activation of p38MAPK and p-p65NF-κB pathways as well as the COX-2 levels in the cerebral cortex, which are indicative of an inflammatory response. Besides, it also reduced the levels of mBDNF, involved in neuroplasticity. Treatment with PSAP restored all these neurochemical alterations induced by LPS. The results demonstrated that PSAP presents antidepressive-like, anxiolytic-like and anti-hyperalgesic effects related to reduction in neuroinflammation., (Copyright © 2018. Published by Elsevier Ltd.)

A novel concept of generating therapeutic gas, nitric oxide (NO) via catalytic phenolic-amine "gallolamine" surface chemistry is developed. The concept is realized using plant polyphenol, gallic acid, and a glutathione peroxidase-like organoselenium compound cystamine or selenocystamine through one-step phenol-amine molecular assembling process. The resulting NO-generating coating with phenolic-cystamine or -selenocystamine framework showed the ability for long-term, steady and controllable range of NO release rates being unparalleled with any existing NO-releasing or NO-generating surface engineering toolkits., Statement of Significance: Developing a facile and versatile strategy for a NO-generating coating with long-term, stable and adjustable NO release is of great interest for the application of blood-contacting materials and devices. Covalent immobilization of glutathione peroxidase (GPx)-like compound to generate NO from a material surface by exposure of endogenously existed S-nitrothiol (RSNO) is a popular strategy. However, it is generally involved in multi-step and complicated processes. Moreover, the amount of immobilized GPx-like compounds is limited by the density of introduced reactive functional groups on a surface. Herein, we propose a novel concept of catalytic plant-inspired gallolamine surface chemistry for material-independent NO-generating coatings. The concept is realized using plant polyphenol, gallic acid, and a GPx-like organoselenium compound cystamine or selenocystamine through one-step phenol-amine molecular assembling process. Without tedious multi-step synthesis, complicated surface treatments, and leakage of toxic chemicals, our unprecedentedly simple, histocompatible and biocompatible phenolic-cystamine or -selenocystamine framework demonstrated long-term, on-demand and facile dose controls of NO generated from the engineering surfaces. These unique features of such a NO-generating coating imparted a material with ability to impressively improve anti-thrombogenicity in vivo. This work constitutes the first report of an interfacial catalytic coating based on material-independent surface chemistry by plant polyphenols. This concept not only expands the application of material-independent surface chemistry in an interfacial catalytic area, but also can be a new platform for antithrombotic materials., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Selenium (Se) shows biologically ambivalent characteristics in animals. It is an essential element but becomes severely toxic when the amount ingested exceeds the adequate intake level. Its biological, nutritional, and toxicological effects are strongly dependent on its chemical form. In this study, we evaluated the toxicity and bioavailability of nine naturally occurring Se compounds, or the so-called bioselenocompounds, in vivo and in vitro. Selenite and selenocystine showed higher toxicity than the other bioselenocompounds in vitro. In an in vitro membrane permeability study using Caco-2 cells, selenomethionine and Se -methylselenocysteine were more efficiently transported than the other bioselenocompounds. The effect of bioselenocompounds on nutritional availability was quantitatively determined from the recovery of serum selenoproteins in Se-deficient rats by speciation analysis. In contrast to the in vitro study, there were no significant differences in the assimilation of Se into serum selenoproteins among the bioselenocompounds, including selenoamino acids, selenosugar, and inorganic Se species, such as selenite, selenate, and selenocyanate, except trimethylselenonium ion. These results indicate that animals can equally assimilate both inorganic and organic naturally occurring selenocompounds except trimethylselenonium ion, which is the urinary metabolite of excess Se. We confirmed that the bioselenocompounds except trimethylselenonium ion had equivalent nutritional availabilities.

Sub-3 nm ultrasmall Bi 2 Se 3 nanodots stabilized with bovine serum albumin were successfully synthesized through a reaction of hydroxyethylthioselenide with bismuth chloride in aqueous solution under ambient conditions. These nanodots exhibit a high photothermal conversion efficiency (η = 50.7%) due to their strong broad absorbance in the near-infrared (NIR) window and serve as a nanotheranostic agent for photoacoustic imaging and photothermal cancer therapy. In addition, they also display radioenhancement with a ratio of 6% due to their sensitivity to X-rays, which makes them a potential sensitizer for radiotherapy. These nanodots were also labled with radioactive 99m Tc for quantification of their biodistribution by single-photon-emission computed tomography (SPECT)/computed tomography (CT) imaging. Our work demonstrates the potential of ultrasmall Bi 2 Se 3 nanodots in multimodal imaging-guided synergetic radiophotothermal therapy of cancer.

We examined two selenorhodamines with amide and thioamide functionality at the 5-position of a 9-(2-thienyl) substituent on the selenoxanthylium analogue of the Texas-red core for their potential as photosensitizers for photodynamic therapy (PDT) in P-glycoprotein (P-gp)-expressing Colo-26 cells. These compounds were examined for their photophysical properties (absorption, fluorescence, and ability to generate singlet oxygen), for their uptake into Colo-26 cells in the absence or presence of verapamil, for their dark and phototoxicity toward Colo-26 cells, and for their co-localization with mitochondrial-specific agents in Colo-26 cells. Both compounds were extremely effective photosensitizers with values of EC50 ⩽ 4 × 10(-8)M toward Colo-26 cells with 1.0 J cm(-2) laser light delivered at 630 ± 2 nm., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: Cardiotoxicity associated with the use of doxorubicin (DOX), and other chemotherapeutics, limits their clinical potential. This study determined the pharmacokinetics and antitumor and cardioprotective activity of free and liposome encapsulated phenyl-2-aminoethyl-selenide (PAESe)., Methods: The pharmacokinetics of free PAESe and PAESe encapsulated in liposomes (SSL-PAESe) were determined in rats using liquid chromatography tandem mass-spectrometry. The antitumor and cardioprotective effects were determined in a mouse xenograft model of human prostate (PC-3) cancer and cardiomyocytes (H9C2)., Results: The encapsulation of PAESe in liposomes increased the circulation half-life and area under the drug concentration time profile, and decreased total systemic clearance significantly compared to free PAESe. Free- and SSL-PAESe improved survival, decreased weight-loss and prevented cardiac hypertrophy significantly in tumor bearing and healthy mice following treatment with DOX at 5 and 12.5 mg/kg. In vitro studies revealed PAESe treatment altered formation of reactive oxygen species (ROS), cardiac hypertrophy and gene expression, i.e., atrial natriuretic peptide and myosin heavy chain complex beta, in H9C2 cells., Conclusions: Treatment with free and SSL-PAESe exhibited antitumor activity in a prostate xenograft model and mitigated DOX-mediated cardiotoxicity.

Ebselen is a synthetic organoselenium compound that has been considered a potential pharmacological agent with low toxicity, showing antioxidant, anti-inflammatory and neuroprotective effects. It is bioavailable, blood-brain barrier permeant and safe based on cellular toxicity and Phase I-III clinical trials. There is evidence that ebselen inhibits acetylcholinesterase (AChE) activity, an enzyme that plays a key role in the cholinergic system by hydrolyzing acetylcholine (ACh), in vitro and ex vivo. This system has a well-known relationship with cognitive process, and AChE inhibitors, such as donepezil and galantamine, have been used to treat cognitive deficits, mainly in the Alzheimer's Disease (AD). However, these drugs have poor bioavailability and a number of side effects, including gastrointestinal upsets and hepatotoxicity. In this way, this study aimed to evaluate the effect of ebselen on cerebral AChE activity in vitro and to determine the kinetic profile and the reversibility of inhibition by dialysis. Ebselen inhibited the cerebral AChE activity with an IC50 of 29 µM, similar to IC50 found with pure AChE from electric eel, demonstrating a mixed and reversible inhibition of AChE, since it increased Km and decreased Vmax. The AChE activity was recovered within 60 min of dialysis. Therefore, the use of ebselen as a therapeutic agent for treatment of AD should be considered, although memory behavior tasks are needed to support such hypothesis.

A novel flavonyl-thiazolidinedione based organoselenocyanate compound was synthesized and established as nontoxic at the doses of 2.5 and 5 mg/kg b.w. in mice. Oral administration of the compound in combination with cyclophosphamide (CP) resulted in an improved therapeutic efficacy which was mostly evidenced in terms of tumor burden and protection of normal cells. The adjuvant therapy was proved to be immensely significant in increasing the mean survivability of the tumor bearing hosts. Reduction in the tumor volume was manifested through the induction of apoptosis and generation of ROS in transformed cells. Moreover, the organoselenium compound could efficiently suppress CP-induced DNA damage, chromosomal aberration, hepatic damage and enhanced the activities of various antioxidant enzymes in normal cells., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

The effects of administering the selenocompounds, sodium selenite, methylseleninic acid (MSA), and seleno-L-methionine (SeMet) on glucose tolerance were compared in the nicotinamide (NA) and streptozotocin (STZ)-induced diabetic mouse model. ICR mice were intraperitoneally treated twice with STZ (100 mg/kg) 15 min after an injection of NA (120 mg/kg) at a 1-d interval. Non-fasting blood glucose levels were then monitored weekly while orally administering the selenocompounds at 158 µg Se/kg body weight with free access to a selenium-deficient diet for 5 weeks. The mean body weights of NA/STZ-induced diabetic mice were partly restored by the administration of selenocompounds, while SeMet led to a higher selenium content and glutathione peroxidase 1 activity in the pancreas. Non-fasting and oral glucose tolerance-tested blood glucose levels, which were elevated by NA/STZ, were significantly suppressed by the administration of SeMet. These results suggest that SeMet may improve glucose tolerance in a NA/STZ-induced mild diabetic mouse model by increasing bioavailability in the pancreas.

Background: Mitochondrial dysfunction contributes to degenerative neurological disorders, consequently there is a need for mitochondria-targeted therapies that are effective within the brain. One approach to deliver pharmacophores is by conjugation to the lipophilic triphenylphosphonium (TPP) cation that accumulates in mitochondria driven by the membrane potential. While this approach has delivered TPP-conjugated compounds to the brain, the amounts taken up are lower than by other organs., Methods: To discover why uptake of hydrophobic TPP compounds by the brain is relatively poor, we assessed the role of the P-glycoprotein (Mdr1a/b) and breast cancer resistance protein (Bcrp) ATP binding cassette (ABC) transporters, which drive the efflux of lipophilic compounds from the brain thereby restricting the uptake of lipophilic drugs. We used a triple transgenic mouse model lacking two isoforms of P-glycoprotein (Mdr1a/1b) and the Bcrp., Results: There was a significant increase in the uptake into the brain of two hydrophobic TPP compounds, MitoQ and MitoF, in the triple transgenics following intra venous (IV) administration compared to control mice. Greater amounts of the hydrophobic TPP compounds were also retained in the liver of transgenic mice compared to controls. The uptake into the heart, white fat, muscle and kidneys was comparable between the transgenic mice and controls., Conclusion: Efflux of hydrophobic TPP compounds by ABC transporters contributes to their lowered uptake into the brain and liver., General Significance: These findings suggest that strategies to bypass ABC transporters in the BBB will enhance delivery of mitochondria-targeted antioxidants, probes and pharmacophores to the brain., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Diabetes mellitus (DM) is a considerably diagnosed metabolic disease and a serious problem worldwide. We prepared various zinc complexes and studied their potential for use as new antidiabetic agents. In this study, we synthesized a seleniferous zinc complex, di(2-selenopyridine-N-oxidato)zinc(II) ([ZPS]) that has a Zn(Se2O2) coordination mode. Analyses of structure-activity relationships between its insulin-like activity and the coordination mode of [ZPS]-related complexes showed that it had high insulin-like activity. Hypoglycemic effects of [ZPS] on type 2 diabetic KK-A(y) mice were exerted at the lowest dose administered (1.25-2.5 mg Zn/kg body weight), unlike previously synthesized zinc complexes. Furthermore, [ZPS] afforded us a new advantage; we were able to investigate the tissue distribution of the ligand by measuring the amount of selenium in the organs of [ZPS]-treated mice. Gastrointestinal absorption and tissue penetration of zinc derived from [ZPS] in ddY mice, which was monitored using an isotope tracer technique, was significantly increased compared to that of ZnCl2. These results suggest that [ZPS] has superior antidiabetic effects compared to previously reported zinc complexes, and is thus a potential novel antidiabetic agent that facilitates the possibility of organoselenium ligands as new metal delivery systems for treating DM., (Copyright © 2013 Elsevier Inc. All rights reserved.)

In spite of an extensive literature reporting pharmacological properties of diphenyl diselenide, (PhSe)(2), little is known about its metabolism. The aim of this study was to identify possible metabolic pathways of (PhSe)(2) in vitro to get insights into the mechanism of its toxicity. Rat liver preparations, namely total homogenate, S9 fraction, cytosol and microsomes were used in the incubations. Samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), high-performance liquid chromatography (HPLC) or inductively coupled plasma (ICP). A reduced glutathione (GSH)-selenol adduct (m/z 462) was identified in all liver fraction incubations by LC-MS/MS, suggesting a reaction between (PhSe)(2) and GSH in tissues. Results from incubation of (PhSe)(2) with microsomal fraction showed that (PhSe)(2) disappears from the supernatant without formation of phase I metabolites. The addition of exogenous GSH maintained constant (PhSe)(2) levels in supernatant and significantly reduced the amount of selenium in the precipitate obtained when microsomal incubations were treated with methanol. Addition of N-acetylcysteine (NAC) had a similar effect; moreover, a NAC-selenol adduct similar to the GSH-selenol adduct was identified by LC-MS/MS (m/z 318) in the NAC incubations. The data indicates that (PhSe)(2) probably binds covalently to microsomal components and that GSH and NAC can prevent binding. The depletion of GSH levels in vitro may be related to (PhSe)(2) toxicity. The inhibition of cytochrome P450 (CYP) activity by carbon monoxide or proadifen did not change the amount of (PhSe)(2) in supernatant and selenium levels in the precipitate, neither did the inactivation of the microsomes by heat indicating that binding was not mediated by cytochrome P450 metabolism and was probably due to a direct reaction between (PhSe)(2) and microsomal components. Due to the covalent binding of (PhSe)(2) to microsomal components the potential of (PhSe)(2) to inhibit cytochrome P450 was examined. (PhSe)(2) at a concentration as low as 1 μM reduced monooxygenase activity with an IC(50) value of 78 μM., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The purpose of this study was to provide data about in vivo tissue distribution and excretion of diphenyl diselenide ((PhSe)₂) in rats and mice through determination of selenium levels in different biological samples. (PhSe)₂ (500 mg/kg, dissolved in canola oil) was administered to animals once a day per oral. After this, mice and rats were housed in metabolic cages (one animal per cage) and urine and feces were collected at specific times after treatment. Three to five animals per group (for each time-point) were anesthetized and blood samples were collected at 0 and 30 min, 24 h, at day 5, 15, and 30 after (PhSe)₂ administration. The plasma and red blood cells were separated. Brain, liver, lungs, kidneys, and adipose tissue were also collected. The determination of selenium levels was performed by inductively coupled plasma atomic emission spectrometry. The main results indicate that: (1) urine is an important route of excretion of selenium originated from (PhSe)₂ in mice and rats; (2) a large amount of (PhSe)₂ or some of its metabolites are stored in fat; (3) the content of selenium found in plasma was low; and (4) liver and kidneys are the tissues with high amounts of selenium.

The goal of this study is to determine whether treatment with methylselenocysteine (MSC) results in differential uptake of irinotecan and its active metabolite (SN-38) between tumors of head and neck squamous cell carcinomas and normal tissue. The in vivo synergy between MSC and irinotecan is influenced by treatment schedule and associated with enhancement of tumor vessel maturation, intra-tumor concentration of SN-38 and apoptotic death of tumor cells. Normal tissue drug concentrations were not impacted by selenium treatment. The finding is of clinical relevance for enabling the delivery of higher doses of irinotecan to reverse tumor resistance, recurrence and ultimately enhancing cure rates., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The recently published report of the SELECT evaluation of selenium and vitamin E provided strong evidence that selenium 200 μg per day in the form of selenomethionine does not protect selenium-replete men against prostate or any other cancer. This seems to refute the result of the much smaller Nutritional Prevention of Cancer (NPC) trial of selenium. Because SELECT did not test the NPC agent, it is possible that the difference between the two trials stems partly from the use of different agents: selenomethionine in SELECT, and selenized yeast in the NPC trial. One of the organic selenium forms suspected of having strong chemopreventive effects, and which may have been present in the NPC agent, is methyl selenocysteine. This study characterizes the single-dose pharmacokinetics of methyl selenocysteine.

The objective of the present study was to describe the uptake and elimination kinetics of selenium (Se) administered in the forms of selenate, selenite, and selenomethionine (seleno-DL-methionine) in different life stages of the midge Chironomus dilutus, and to determine the relationship between Se bioavailability and Se speciation using X-ray absorption spectroscopy (XAS). Midge larvae exposed to 4.3 µg/L as dissolved selenate for 10 d of had negligible accumulation of Se (indistinguishable from control organisms). However, larvae rapidly accumulated Se over 10 d of exposure to 3.8 and 1.8 µg/L selenite and seleno-DL-methionine (Se-met), respectively. Most Se accumulated by larvae exposed to selenite or Se-met was retained after 10 d of elimination in clean water. When additional midge larvae were exposed to Se until emergence, Se accumulated during the larval stage was largely retained in the adults. Although a strong correlation was found between the adult whole-body Se concentration and the Se concentration in the exuvia after emergence, only a minor loss of Se occurred in the shed exuvia compared with larvae and adult whole-body concentrations. X-ray absorption spectroscopy analysis showed that organic selenides and diselenides, modeled as Se-met and selenocystine, respectively, were the dominant forms of Se in both the larval and adult insect stages. The proportion and concentration of organic selenides (selenomethionine) increased in larvae and adults exposed to Se-met and selenite compared with larvae exposed to selenate, whereas the concentration of diselenides (selenocystine) remained relatively constant for all treatments., (Copyright © 2011 SETAC.)

The distribution and metabolism of selenohomolanthionine (4,4'-selenobis[2-aminobutanoic acid], SeHLan), a newly identified selenoamino acid in selenized Japanese pungent radish, were evaluated by administering ⁷⁷Se-labeled SeHLan at a dose of 25 μg/kg body weight in rats. Exogenous ⁷⁷Se of SeHLan was preferably distributed to the kidneys and remained in the intact form for up to 6 h after dosing. The accumulation in the kidneys is one of the specific characteristics of SeHLan, differing from other selenoamino acids, such as selenomethionine and Se-methylselenocysteine, which preferably accumulate in the pancreas. The intact form of SeHLan was detected in the serum and kidney supernatant but not in the urine, suggesting that the amount of exogenous Se that was distributed to the kidneys was within metabolic capacity. Indeed, the exogenous Se was converted into two urinary metabolites, Se-methylseleno-N-acetyl-galactosamine and trimethylselenonium. Exogenous Se was also detected in several selenoproteins, including selenoprotein P and extracellular glutathione peroxidase. SeHLan is expected to be a potential supplemental source of Se because its distribution differs from that of selenomethionine and Se-methylselenocysteine.

Although in vitro data from our previous studies show that the antioxidant effect and reactions of both diphenyl diselenide (DPDS) and dicholesteroyl diselenide (DCDS) towards thiol-containing proteins differ considerably, the present study sought to evaluate the interaction of both organodiselenides with thiol-containing proteins in vivo. Mice were injected subcutaneously with DPDS or DCDS previously dissolved in soya bean oil at doses of 0.5 mmol kg⁻¹ body weight for four consecutive days. The activities of delta aminolevulinic acid dehydratase (ALA-D), Na+/K+-ATPase, and isoforms of lactate dehydrogenase (LDH) and catalase were investigated. In addition, the antioxidant status of the mice was determined by measuring the levels of glutathione (GSH), vitamin C (Vit C) and thiobarbituric acid reactive substances. The results show that both diselenides significantly increased the levels of GSH and Vit C but did not markedly alter other antioxidant indices. With respect to the thiol-containing enzymes that were evaluated, DPDS and not DCDS caused a marked reduction in the activities of hepatic ALA-D; however, both diselenides inhibited all isoforms of LDH evaluated. In addition, the activities of cerebral Na+/K+-ATPase were not markedly inhibited by both diselenides, suggesting that this cerebral enzyme may not be a molecular target of organodiselenides toxicity. Taken together, the pharmacological and toxicological chemistry of organoselenium compounds is complex and multifactorial and is dependent on delicate equations which include vehicle solution, animal species and mode of delivery., (Copyright © 2010 John Wiley & Sons, Ltd.)

Because the Selenium (Se) and Vitamin E Cancer Prevention Trial (SELECT) failed to show the efficacy of selenomethionine for prostate cancer prevention, there is a critical need to identify safe and efficacious Se forms for future trials. We have recently shown significant preventive benefit of methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) in the transgenic adenocarcinoma mouse prostate (TRAMP) model by oral administration. The present work applied iTRAQ proteomic approach to profile protein changes of the TRAMP prostate and to characterize their modulation by MSeA and MSeC to identify their potential molecular targets. Dorsolateral prostates from wild-type mice at 18 weeks of age and TRAMP mice treated with water (control), MSeA, or MSeC (3 mg Se/kg) from 8 to 18 weeks of age were pooled (9-10 mice per group) and subjected to protein extraction, followed by protein denaturation, reduction, and alkylation. After tryptic digestion, the peptides were labeled with iTRAQ reagents, mixed together, and analyzed by two-dimensional liquid chromatography/tandem mass spectrometry. Of 342 proteins identified with >95% confidence, the expression of 75 proteins was significantly different between TRAMP and wild-type mice. MSeA mainly affected proteins related to prostate functional differentiation, androgen receptor signaling, protein (mis)folding, and endoplasmic reticulum-stress responses, whereas MSeC affected proteins involved in phase II detoxification or cytoprotection, and in stromal cells. Although MSeA and MSeC are presumed precursors of methylselenol and were equally effective against the TRAMP model, their distinct affected protein profiles suggest biological differences in their molecular targets outweigh similarities., (2010 AACR.)

The retention behavior of selenites, selenates, seleno-DL-methionine, selenocystine, selenocystamine, selenourea, dimethyl selenide, and dimethyl diselenide was investigated by means of biomimetic liquid chromatography. For this purpose, two immobilized artificial membrane (IAM) columns, namely, IAM.PC.DD2 and IAM.PC.MG, and two immobilized plasma protein columns, human serum albumin (HSA) and alpha(1)-acid glycoprotein (AGP) columns, were employed using different mobile phase conditions in respect to pH and buffer composition. In general, satisfactory interrelations between retention factors obtained with the two IAM stationary phases and HSA/AGP columns were obtained. Large differences were observed between biomimetic retention factors and octanol-water logD values, since the latter fail to describe electrostatic interactions. In contrast, despite the column diversity, the net retention outcome on all four biomimetic columns was quite similar, especially in the presence of phosphate-buffered saline, which by its effective shielding alleviates the differences between the stationary phases. Of the two IAM columns, IAM.PC.DD2 showed better performance when compared with HSA and AGP columns as well as to octanol-water partitioning. Biomimetic chromatographic indices were further used to estimate the percentage of human oral absorption and plasma protein binding of the eight selenium species investigated, according to equations previously reported in the literature. The estimated values of human oral absorption imply moderate absorption only for dimethyl diselenide, which also may exhibit considerable plasma protein binding. Moderate affinity for plasma proteins should also be expected for dimethyl selenide and selenocystamine.

BBSKE (1,2-[bis(1,2-benzisoselenazolone-3(2H)-ketone)] ethane, PCT: CN02/00412) is a novel organoselenium anticancer drug that plays a role in anticancer through inhibiting TrxR (thioredoxin reductase). In this study, we prepared a tri-block copolymer micelles loading BBSKE utilizing the amphiphilic tri-block copolymers (PEG6000-PLA6000) which we synthesized. And then the characters of the copolymer micelles were investigated. When packaged in polymeric micelles, the water solubility of BBSKE was improved to 0.21 mg/ml. The IC(50) were 7.14 microM, 5.05 microM and 4.23 microM when MCF-7 breast cancer cells were treated with BBSKE after 24h, 48h and 72h. The inhibition effect of polymeric micelles to MCF-7 tumor cells was bettered when folate, whose receptor was highly expressed in various tumors, was coated on the surface of these nanoparticles. Finally, by adopting a new way of imaging in vivo, we studied the distribution of micelles in nude mice with and without MCF-7 tumor. The results demonstrated that this copolymer micelles loading BBSKE can accumulate into tumor efficiently., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Diphenyl diselenide [(PhSe)2], an organoselenium compound, presents toxicological effects in rat pups, manifested by the appearance of seizure episodes. The aim of this study was to carry out the determination and quantification of (PhSe)2 in plasma, liver and brain of rat pups after oral administration (p.o) of this compound (500 mg/kg). The second objective of this study was to correlate the latency to the appearance for the first seizure episode with (PhSe)2 plasma, liver and brain levels. Analysis of (PhSe)2 in plasma, liver and brain samples was performed by gas chromatography/flame ionized detector system (GC/FID). The average levels of (PhSe)2 in plasma, liver and brain of rat pups were 3.67, 5.07 and 1.15 microg/ml, respectively, at 20.58 min post dosing, the latency media for the first seizure episode. (PhSe)2 levels in plasma did not correlate with the latency for the first seizure episode induced by this compound. A significant negative correlation between the latency for the first seizure episode and the levels of (PhSe)2 liver and brain of rat pups was found. It demonstrates that rat pups which had highest levels of (PhSe)2 in liver and brain showed the shortest latency for the first seizure episode.

Se-methylselenocysteine (MeSeCys) is not only a selenium (Se) supplement but also a more promising precursor of an anti-tumor drug containing Se than selenomethionine, which is currently used as Se supplement. In this study, the metabolism of MeSeCys labeled with an Se isotope, 82Se, in rats depleted of endogenous natural abundance isotopes with another Se isotope, 78Se, was traced for 21 days when MeSeCys was continuously and perorally ingested at a supplemental dose. The tracer experiment was performed with our improved method that utilized an inductively coupled plasma-deuterium reaction-mass spectrometer. The substitution of endogenous Se with a single isotope, 78Se, facilitated the detection of exogenous labeled Se. Exogenous Se in the form of MeSeCys preferably accumulated and/or assimilated in the liver, kidneys and testes with long-term ingestion of MeSeCys and was utilized for the synthesis of selenoproteins, i.e., extracellular and cellular glutathione peroxidases and selenoprotein P. Meanwhile, intact MeSeCys was not excreted into urine although trimethylselenonium was detected in addition to selenosugar. The results suggest that MeSeCys was transformed into selenide via methylselenol by beta-lyase. Consequently, it is surmised that MeSeCys is a precursor of methylselenol under long-term ingestion.

A rapid and sensitive liquid chromatography/electrospray ionization tandem mass spectrometric (LC/ESI-MS/MS) method has been developed to determine 1, 2-[bis(1,2-benzisoselenazolone-3(2H)-ketone)]-ethane (BBSKE), a novel antineoplastic agent, in rat plasma. The analytes were separated on a C18 column with a mobile phase of methanol-water (75:25, v/v) and detected using a triple-quadrupole mass spectrometer in positive mode with the selective reaction monitoring. The characteristic ion dissociation transitions were m/z 603.0 --> 448.9 for derivatized BBSKE and m/z 631.0 --> 476.8 for derivatized internal standard. The assay was linear over a range of 1-1000 ng/mL with a lower limit of quantification of 1 ng/mL. Intra- and inter-day precisions were less than 9.6 and 5.0%, respectively, and the accuracy ranged from -5.2 to 4.0%. The validated method was successfully applied to the characterization of pharmacokinetic profile of BBSKE after oral administration in rats. Cop

It has been proposed that Se-methylselenocysteine (MeSeCys) and methylseleninic acid (MSA(IV)) are efficiently transformed through the beta-lyase and reduction reactions, respectively, into methylselenol, the assumed biologically active selenometabolite responsive for the anti-carcinogenicity and anti-oxidant actions of selenium. The bioavailability and distribution of the two selenium sources in major organs/tissues were compared under exactly identical conditions. Namely, labeled selenium sources (76)Se-MeSeCys and (77)Se-MSA(IV), at a single oral dose of 10 microg Se/kg body weight each, were administered simultaneously to rats that had been depleted of natural abundance selenium with a single isotope (78)Se. The same dose of (82)Se-selenite was also administered as a reference selenium source. The distributions of the three labeled selenium isotopes were determined 3 h after the administration in 13 organs/tissues/blood. MeSeCys was taken up more efficiently by most organs, especially the pancreas and duodenum, than MSA(IV) and selenite, the latter two sources being taken up similarly to each other except for in the kidney, liver, and spleen, where the three labeled isotopes were detected at comparable concentrations. The labeled selenium in the liver supernatant was speciated by HPLC inductively coupled argon plasma-mass spectrometry (ICP-MS), and it was suggested that MeSeCys was delivered in its intact form to organs, and then transformed into methylselenol. In addition to the known properties of that MeSeCys is chemically more stable than MSA(IV) and is a naturally occurring edible product, and that MeSeCys produces methylselenol much more efficiently than a homologous selenoamino acid selenomethionine, the present study revealed that MeSeCys is more efficiently distributed than MSA(IV) in its intact form, and then produces methylselenol, suggesting that MeSeCys is the best methylselenol source in most organs/tissues.

Purpose: Our previous work has shown that methylseleninic acid (MSeA) sensitized hormone refractory prostate cancer (HRPCa) cells to apoptosis induced by paclitaxel (Taxol) through enhancing multiple caspases. This study aimed to (a) determine the general applicability of the sensitization effect for taxane drugs in vitro, (b) establish the enhancement of paclitaxel efficacy by MSeA in vivo, and (c) investigate Bcl-XL and survivin as molecular targets of MSeA to augment apoptosis., Experimental Design: DU145 and PC-3 HRPCa cell lines were used to evaluate the in vitro apoptosis effects of paclitaxel, docetaxel and their combination with MSeA, and the molecular mechanisms. DU145 xenograft growth in athymic nude mice was used to evaluate the in vivo efficacy of paclitaxel and its combination with MSeA. The tumor samples were used to examine Bcl-XL and survivin protein abundance., Results: MSeA combination with paclitaxel or docetaxel exerted a greater than additive apoptosis effect on DU145 and PC-3 cells. In nude mice, paclitaxel and MSeA combination inhibited growth of DU145 subcutaneous xenograft with the equivalent efficacy of a four-time higher dose of paclitaxel alone. MSeA decreased the basal and paclitaxel-induced expression of Bcl-XL and survivin in vitro and in vivo. Ectopic expression of Bcl-XL or survivin attenuated MSeA/paclitaxel-induced apoptosis., Conclusions: MSeA enhanced the efficacy of paclitaxel against HRPCa in vitro and in vivo, at least in part, by down-regulating the basal and paclitaxel-induced expression of both Bcl-XL and survivin to increase caspase-mediated apoptosis. MSeA may be a novel agent to improve taxane combination therapy.

A series of selenophene analogues of the thiophene-containing antihypertensives milfasartan and eprosartan were prepared and tested for AT(1) receptor antagonist properties. All four selenophene compounds proved to be potent AT(1) receptor antagonists, with pK(B) estimates indicating that these selenides are at least as effective as the thiophene parent compounds at blocking AT(1) receptor mediated responses. These results reveal that replacement of sulfur with selenium in thiophene-containing sartans does not interfere with sartan activity.

There was conducted a comparative study of organic and inorganic selenium forms bioavailability and of an influence of said trace elements safety on growth parameters and glutathione peroxidase activity in male wister rats. The results obtained confirmed an advance of organic selenium use (as an enzymatic yeast hydrolysate) on comparison to it's inorganic form (sodium selenite).

The biological availability and metabolism of two selenosugars orally administered to rats were investigated. Two other selenium species, selenite and trimethylselenonium ion (TMSe) were included in the study as positive and negative controls, respectively. Male Wistar strain rats (three per group) at 8 weeks of age were exposed to sodium selenite, TMSe, selenosugar 1 (methyl-2-acetamido-2-deoxy-1-seleno-beta-D-galactopyranoside) or selenosugar 2 (methyl-2-acetamido-2-deoxy-1-seleno-beta-D-glucopyranoside) through drinking water for 48 h. Total selenium concentrations (ICPMS) and selenium species concentrations (HPLC/ICPMS) were determined in urine samples collected in two 24h periods during the exposure, and total selenium concentrations in liver, kidney, small intestine and blood were determined at the end of the experiment. The major species found in background urine were selenosugar 1 (major metabolite) and TMSe (minor metabolite). Rats exposed to selenite excreted large quantities of selenosugars and TMSe consistent with efficient uptake and biotransformation of selenite, whereas TMSe-exposed rats excreted large quantities of TMSe, but there was no significant increase of other selenium metabolites, consistent with TMSe being taken up and excreted unchanged. Rats exposed to selenosugars, however, excreted significant quantities of TMSe suggesting that the sugars were at least partly biologically available and biotransformed. Rats exposed to selenite accumulated selenium in the liver, kidney, small intestine and blood, whereas no accumulation was observed for the other samples except for small increases in selenium concentrations of small intestine from the two selenosugar-exposed groups.

Selenium compounds, like diphenyl diselenide (Ph(2)Se(2)), possess glutathione peroxidase (GSHPx)-like activities and other antioxidant properties. The aim of this study was to evaluate the effects of a long-term oral supplementation with Ph(2)Se(2) on various toxicological parameters in rabbits. Adult New Zealand male rabbits were divided into four groups: Group I served as control; Groups II, III and IV received 0.3, 3.0 and 30 p.p.m. of Ph(2)Se(2) pulverized in the chow for 8 months. A number of toxicological parameters were examined in liver, kidney, cerebral cortex and hippocampus, such as delta-aminolaevulinic acid dehydratase (delta-ALA-D), catalase (CAT), GSHPx activities, non-protein thiol (-SH), lipid peroxidation and ascorbic acid levels. The results indicated that supplementation 30 p.p.m. Ph(2)Se(2 )significantly increased delta-ALA-D activity in liver and in cerebral cortex. Non-protein -SH levels were significantly increased in liver but not in kidney, cerebral cortex and hippocampus of rabbits. Ascorbic acid content was significantly lower in the liver and cerebral cortex after supplementation with 30 p.p.m. Ph(2)Se(2). Conversely, no alterations in GSHPx and CAT activities, nor in thiobarbituric acid reactive substances levels were observed in rabbit tissues. These results indicate that oral supplementation with Ph(2)Se(2) is relatively secure in rabbits after 8 months of exposure. The findings encourage further experiments on the potential therapeutic effects of such compound.

A novel HPLC-UV method with pre-column derivatization by using 2-mercaptoethanol was established for determination of 1,2-[bis(1,2-benzisoselenazolone-3(2H)-ketone)]-ethane (BBSKE) in dog plasma. The derivatives were identified by mass spectrometry. The method had a good linear range of 0.05-2 microg/ml (r(2)=0.9995). The lower limit of quantification (LOQ) was 0.05 microg/ml. The precision and accuracy were less than 7%. After dosing of BBSKE (30 mg/kg, p.o. and 0.79 mg/kg, i.v.) in dogs, AUC(0-t) were 5.72+/-2.42 and 1.35+/-0.41 microg h/ml; t(1/2) were 4.6+/-2.1 and 1.7+/-0.6h, respectively. The method was successfully applied to the pharmacokinetic study in dogs.

Se-Methylated selenoamino acids, Se-methylselenocysteine (MeSeCys) and selenomethionine (SeMet), are chemically inert storage forms of selenium in selenium-accumulators, and a nutritional and supplemental source. The metabolic pathway for MeSeCys was precisely traced by referring to those for SeMet and selenite by applying a new tracer method involving multiple homo-elemental stable isotopes. Male Wistar rats were depleted of endogenous natural abundance selenium with a single (80)Se-enriched isotope, and then (76)Se-MeSeCys, (77)Se-SeMet and (82)Se-selenite were orally administered simultaneously at 25 microg Se/kg body weight each. Organs and body fluids were obtained at 3, 6, 9 and 12 h, and 1 and 2 days later, and subjected to speciation analysis. The main characteristics of the metabolism were as follows; MeSeCys was incorporated into selenoprotein P slightly more than or at a comparable level to that of SeMet but less than that of selenite. MeSeCys and SeMet but not selenite was taken up by organs in their intact forms. MeSeCys and SeMet were delivered specifically to the pancreas and present in a form bound to an identical or similar protein. Trimethylselenonium (TMSe) was only produced from MeSeCys, i.e., not from SeMet or selenite, in the kidneys. Both selenosugars A and B of MeSeCys, SeMet and selenite origin were detected in the liver but only selenosugar B in the kidneys. These results suggest that MeSeCys can be a similar or better selenium source than SeMet, and supplies methylselenol much more efficiently in organs than SeMet and selenite. TMSe was produced much efficiently from MeSeCys than from SeMet and selenite, suggesting a role of methylselenol through the beta-lyase reaction in the metabolism of Se-methylated selenoamino acids.

Background: Some plants hyperaccumulate the toxic element selenium (Se) to extreme levels, up to 1% of dry weight. The function of this intriguing phenomenon is obscure., Results: Here, we show that the Se in the hyperaccumulator prince's plume (Stanleya pinnata) protects it from caterpillar herbivory because of deterrence and toxicity. In its natural habitat, however, a newly discovered variety of the invasive diamondback moth (Plutella xylostella) has disarmed this elemental defense. It thrives on plants containing highly toxic Se levels and shows no oviposition or feeding deterrence, in contrast to related varieties. Interestingly, a Se-tolerant wasp (Diadegma insulare) was found to parasitize the tolerant moth. The insect's Se tolerance mechanism was revealed by X-ray absorption spectroscopy and liquid chromatography-mass spectroscopy, which showed that the Se-tolerant moth and its parasite both accumulate methylselenocysteine, the same form found in the hyperaccumulator plant, whereas related sensitive moths accumulate selenocysteine. The latter is toxic because of its nonspecific incorporation into proteins. Indeed, the Se-tolerant diamondback moth incorporated less Se into protein. Additionally, the tolerant variety sequestered Se in distinct abdominal areas, potentially involved in detoxification and larval defense to predators., Conclusions: Although Se hyperaccumulation protects plants from herbivory by some invertebrates, it can give rise to the evolution of unique Se-tolerant herbivores and thus provide a portal for Se into the local ecosystem. In a broader context, this study provides insight into the possible ecological implications of using Se-enriched crops as a source of anti-carcinogenic selenocompounds and for the remediation of Se-polluted environments.

Nutritional selenocompounds are considered to be transformed into the common intermediate selenide for utilization as selenoenzymes and/or for excretion as selenosugar and trimethylselenonium (TMSe). Therefore, selenocompounds can only be traced with a labeled selenium atom. Methylseleninic (MSA(IV)) has been proposed to be a third nutritional selenium source, the other two being inorganic selenocompounds and organic selenoamino acids, and to be a proximate selenochemical for producing the assumed biologically active form methylselenol. Here we applied a new tracer method to compare the availability and metabolism of MSA(IV) with those of three related selenocompounds under exactly identical host and tracing conditions. (82)Se-Selenite, (78)Se-selenate, (77)Se-MSA(IV) and (76)Se-methylselenonic acids (MSA(VI)) were simultaneously administered orally, each at the dose of 25 microg Se/kg body weight, to rats that had been depleted of endogenous natural abundance selenium with a single stable isotope ((80)Se). Time-related changes in the concentrations and/or distributions of the four labeled isotopes in the serum, liver, kidney, pancreas, lung and urine were determined simultaneously by inductively coupled argon plasma mass spectrometry (ICP MS) and/or HPLC-ICP MS. The availability with different isotope ratios was in the decreasing order of selenate>selenite=MSA(IV)>MSA(VI). Although selenate and MSA(VI) were distributed in organs and urine partly in their intact forms, MSA(IV) and selenite were not detected in the intact forms at all. MSA(IV) and MSA(VI) but not selenite or selenate produced TMSe in organs other than the liver, suggesting the transformation of MSA(IV) into methylselenol, and then either into selenide for the synthesis of selenoproteins and selenosugar or directly into TMSe. Thus, selenosugar and TMSe were produced widely in the organs. However, TMSe was not detected in the liver. The organ- and selenium source-specific production of TMSe was discussed as to the differences in selenium sources, and demethylation and methylation activity.

Nutritional selenium compounds are transformed to the common intermediate selenide and then utilized for selenoprotein synthesis or excreted in urine mostly as 1beta-methylseleno-N-acetyl-Dd-galactosamine (selenosugar). Since the biological significance of selenosugar formation is unknown, we investigated their role in the formation of selenoenzymes in selenium deficiency. Rats were depleted of endogenous natural abundance selenium with a single stable isotope ((82)Se) and then made Se-deficient. (76)Se-Selenosugar was administered intravenously to the rats and their urine, serum, liver, kidneys and testes were subjected to speciation analysis with HPLC inductively coupled argon plasma mass spectrometry. Most (76)Se was recovered in its intact form (approximately 80% of dose) in urine within 1 h. Speciation analysis revealed that residual endogenous natural abundance selenium estimated by (77)Se and (78)Se was negligible and distinct distributions of the labeled (76)Se were detected in the body fluids and organs without interference from the endogenous natural abundance stable isotope. Namely, intact (76)Se-selenosugar was distributed to organs after the injection, and (76)Se was used for selenoprotein synthesis. Oxidation to methylseleninic acid and/or hydrolysis of the selenoacetal group to methylselenol were proposed to the transformation of selenosugar for the reuse. Effective use of an enriched stable isotope as an absolute label in hosts depleted of natural abundance isotopes was discussed for application in tracer experiments.

HEK293T cells overexpressing divalent metal transporter-1 (DMT1) were established to screen for small-molecule inhibitors of iron uptake. Using a fluorescence-based assay, we tested 2000 known bioactive compounds to find 3 small molecules that potently block ferrous iron uptake. One of the inhibitors, ebselen, is a seleno compound used in clinical trials as a protective agent against ischemic stroke. Ebselen inhibited Fe(II) uptake (IC(50) of approximately 0.22 microM), but did not influence Fe(III) transport or DMT1-mediated manganese uptake. An unrelated antioxidant, pyrrolidine dithiobarbamate (PDTC), also inhibited DMT1 activity (IC(50) of approximately 1.54 microM). Both ebselen and PDTC increased cellular levels of reduced glutathione. These observations indicate that Fe(II) transport by DMT1 can be modulated by cellular redox status and suggest that ebselen may act therapeutically to limit iron-catalyzed damage due to transport inhibition.

Methylseleninic acid (MSA(IV)) [CH(3)Se(O)OH] is readily reducible to methylselenol [CH(3)SeH], the assumed lyase metabolite and the proposed biologically active form of methylated selenoamino acids. At the same time, MSA(IV) is an oxidation product of the major urinary metabolite selenosugar. (77)Se-Enriched MSA(IV) was injected intravenously into rats (25 microg Se/kg body weight), and urine, blood and liver were obtained at five time points after the injection. Time-related changes in the concentration of (77)Se were determined together with speciation analysis of the labeled metabolites. (77)Se was mostly moved into red blood cells (RBCs) within 10 min, and then redistributed into organs within 30 min. Excessive (77)Se taken up by the liver was first detected as selenosugar A and then as B, suggesting that MSA(IV) was transformed to selenide, and then to selenosugar A followed by methylation to selenosugar B (urinary metabolite). (77)Se was incorporated also into selenoproteins (most efficiently to plasma selenoprotein P that is synthesized in liver), suggesting that MSA(IV) is utilized for the synthesis of selenosugar (for excretion) and selenoproteins (for utilization) through selenide. In vitro experiments with simultaneous incubation of (77)Se-MSA(IV) and (82)Se-selenite in a RBC suspension revealed the precise difference in the metabolism between MSA(IV) and selenite in RBCs. (77)Se excreted into the urine was mostly detected as selenosugar but with a distinct amount of trimethylselenonium, suggesting that selenosugar and trimethylselenonium are produced depending on the capacity to transform methylselenol to selenide. MSA(IV) was suggested to be reduced to methylselenol (allowing the production of a proposed active form of selenium), and then transformed (demethylated) to selenide for utilization and excretion.

1. The aim of the present study was to investigate the effects on the eggs and hatchlings (up to 2 weeks post-hatch) of feeding a relatively large amount of so-called organic selenium to breeder quail. 2. Two groups of quail (3 families in each group consisting of 4 females and 1 male) were formed at the beginning of their reproductive period. The quail were fed on a commercial maize-based diet containing 0.096 mg/kg feed-derived selenium (Se), supplemented with 0.2 mg/kg selenite (control group) or 0.5 mg/kg organic selenium in the form of Sel-Plex (Alltech Ltd, USA) for 6 months. Eggs were collected at 6 months of age and Se in the egg yolk, egg white and shell was analysed. Five quail at 1, 7 and 14 d post-hatch were killed to provide samples of liver, brain, breast and leg muscles for Se analysis. After egg collection for analysis and incubation, adult quail were killed and liver, kidney, lung, brain, breast and leg muscles were collected for Se analyses. 3. Inclusion of high doses (0.5 mg/kg) of organic Se in the quail diet was associated with a significant increase in Se concentration in all tissues studied of adult quail as well as in egg yolk, egg albumin and eggshell. 4. Increased Se concentration in the quail egg was associated with increased Se concentration in the liver, breast and leg muscles and brain of newly hatched quail. This difference was shown to be significant for 2 weeks post-hatch. Therefore, it has been suggested that the maternal effect of dietary selenium can be seen beyond the hatching time and more emphasis should be given to this effect in future. 5. It was shown that it is possible to produce Se-enriched quail meat and eggs by adding organic selenium to the diet.

We have previously reported that (4R,5R)-5-ethyl-2-imino-4-methylthiazolidine (3) strongly inhibits inducible nitric oxide synthase (iNOS). In a successive search for strong and selective iNOS inhibitors, we, herein, describe the synthesis of the selenium analogue of 3 (4: ES-2133) and its related optically active compounds and examine their in vitro and in vivo inhibitory activity against iNOS. In addition, an alternative synthetic method to the selected compound 4 and its pharmacokinetic profile is also reported.

The mechanism of delta-aminolevulinate dehydratase (delta-ALA-D) inhibition by phenyl selenoacetylene in vitro was investigated in this study. Phenyl selenoacetylene (40-400 microM) inhibition of delta-aminolevulinate dehydratase from rat liver (low speed supernatant fraction, S1 fraction) was partially prevented by incubation under argon atmosphere and completely prevented by dithiothreitol. After incubation with S1 fraction from rat liver or cysteine (40 mM), phenyl selenoacetylene was partially converted into diphenyl diselenide, which is a stronger inhibitor of delta-aminolevulinate dehydratase than phenyl selenoacetylene. Diphenyl diselenide increased the rate of oxidation of -SH groups, while phenyl selenoacetylene did not affect such oxidation. delta-Aminolevulinate dehydratase purified from bovine liver (Sigma) was less sensitive to phenyl selenoacetylene and diphenyl diselenide than the enzyme from S1 fraction. We propose that the lower sensitivity of purified enzyme to selenides could be related to the formation of selenols due to the presence of dithiothreitol (a reducing agent) in the incubation medium. In agreement, incubation of purified enzyme (Sigma) with diphenyl diselenide (2 microM) and sodium borohydride (a reducing agent) under argon atmosphere significantly increased enzyme activity. Results obtained suggest that delta-aminolevulinate dehydratase inhibition by phenyl selenoacetylene is dependent on its conversion into diphenyl diselenide that induces oxidation of essential -SH groups of delta-aminolevulinate dehydratase. We propose that oxygen could be important in the regeneration of diphenyl diselenide leading to a catalytic oxidation of the enzyme.

We have previously reported the synthesis and characterization of two new classes of selenazolidine-4(R)-carboxylic acids (2-oxo and 2-methyl-SCAs) (OSCA and MSCA, respectively), as well as the "parent" compound, selenazolidine-4(R)-carboxylic acid (SCA, selenaproline). These compounds were designed as prodrugs of L-selenocysteine with potential application in cancer chemoprevention or other clinical uses. We will be exploring the chemopreventive activity of the new compounds in the well-established A/J mouse model of tobacco-induced lung carcinogenesis. The objectives of the present study were to investigate several fundamental biochemical endpoints after selenazolidine administration compared with other selenium-containing agents. Groups of mice were fed either AIN-76A diet alone or the diet supplemented with the following selenium compounds (ppm Se): sodium selenite (5), L-selenomethionine (3.75), L-selenocystine (15), Se-methyl-L-selenocysteine (3), MSCA (5, 10, or 15), OSCA (5, 10, or 15), or SCA (5, 10, or 15). After 28 days of supplementation, toxicity of the selenazolidines was not evident, as measured by outward appearance and behavior, body and organ weight changes, and histological evaluation of liver and lung tissue. Select treatment groups showed significant increases in selenium levels in blood and tissues. Increased activity of selenium-dependent glutathione peroxidase (GPx) in blood and liver illustrated that the selenazolidines provided a source of biologically-available selenium.