Suppression of Tumor Growth in a Rabbit Hepatic Cancer Model by Boron Neutron Capture Therapy With Liposomal Boron Delivery Systems.

BACKGROUND/AIM: Tumor cell destruction by boron neutron capture therapy (BNCT) is attributed to the nuclear reaction between 10B and thermal neutrons. The accumulation of 10B atoms in tumor cells without affecting adjacent healthy cells is crucial for effective BNCT. We previously reported that several types of liposomal boron delivery systems (BDS) delivered effective numbers of boron atoms to cancer tissues, and showed tumor-growth suppression after thermal neutron irradiation. In the present study, we examined the effects of BNCT after intra-arterial infusion of 10B-borono-dodecaborate (10BSH) by liposomal BDS in rabbit hepatic cancer models. MATERIALS AND METHODS: We prepared 10BSH-entrapped transferrin-conjugated polyethylene glycol liposomes constructed with distearoyl-boron lipid (TF-PEG-DSBL), and performed thermal neutron irradiation at the Kyoto University Institute for Integrated Radiation and Nuclear Science after intra-arterial infusion into rabbit VX-2 hepatic tumors. RESULTS: Concentrations of 10B in VX-2 tumors on delivery with TF-PEG-DSBL liposomes reached 25 ppm on day 3 after the injection. Tumor growth was suppressed by thermal neutron irradiation after intra-arterial injection of this 10BSH-containing liposomal BDS, without damage to normal cells. CONCLUSION: The present results demonstrate the applicability of 10B-containing TF-PEG-DSBL liposomes as a novel intra-arterial boron carrier in BNCT for cancer.

Hair Metal Levels and Childhood Weight Gain.

BACKGROUND: Exposure to toxic metals remains a public health problem with lifelong impacts on childhood growth and development. We aimed to investigate metals effects on preschool children's anthropometric variables. METHODS: The study was conducted in Tehran, Iran, from Jul 2013 to Mar 2016. We measured scalp hair metal concentrations (lead, cadmium, arsenic, zinc, manganese, and cobalt), using inductively coupled plasma mass spectrometry, in 207 preschool children's (36 to 72 months old). RESULTS: A significant negative correlation between children's hair lead levels and children's weight was found (r= -0.178, P<0.05). Linear regression analysis confirmed the relationship when adjusted for the confounders, including children's age, sex, height, family income, and maternal education (ß= -0.191; t= -3.426, P< 0.01). The ANOVA analysis showed a significant (P<0.01) difference between hair lead level and children's weight-for-age percentiles. Totally and separately, in almost all weight percentiles, hair lead levels were higher in girls than boys. CONCLUSION: The present study on Iranian children showed the current levels of lead exposure might negatively influence on children growth, with higher risk for girls than boys.

Single-dose toxicity study by intra-arterial injection of 10BSH entrapped water-in-oil-in-water emulsion for boron neutron capture therapy to hepatocellular carcinoma.

We developed a mixing medical device by attaching Shirasu porous glass Millipore membrane to prepare water-in-oil-in-water (WOW) emulsion in a shorter time to be applied as 10B-entrapped WOW emulsion for hepatocellular carcinoma (HCC) treatment. Single-dose toxicity studies by intra-arterial injection of 10BSH-entrapped WOW were performed in rabbits and pig, and no side effects were observed. We hope to proceed to the preclinical and clinical studies for further evaluation of 10B compound as multidisciplinary treatments for HCC.

Changes in thallium distribution in the scalp hair after an intoxication incident.

In cases of criminal thallium poisoning, forensic investigation is required to identify the amount and time of thallium exposure. Usually, blood and urine thallium levels are respectively used as biomarkers. Additionally, hair has the unique potential to reveal retrospective information. Although several studies have attempted to clarify how thallium is distributed in hair after thallium poisoning, none have evaluated the time course of changing thallium distribution. We investigated changes in the distribution of thallium in hair at different time points after exposure in five criminal thallotoxicosis patients. Scalp hair samples were collected twice, at 2.6 and 4.2-4.5months after an exposure incident by police. Results of our segmented analysis, a considerable amount of thallium was detected in almost all hair sample segments. The thallium exposure date estimated from both hair sample collections matched the actual exposure date. We found that determination of thallium amounts in hair samples divided into consecutive segments provides valuable information about exposure period even if a considerable time passes after exposure. Moreover, when estimating the amount of thallium exposure from a scalp hair sample, it is necessary to pay sufficient attention to individual differences in its decrease from hair.

Effects of Hair Metals on Body Weight in Iranian Children Aged 20 to 36 Months.

BACKGROUND: Although the level of exposure to many toxic metals decreased recently, the adverse effects of these metals on children's growth and development remain a serious public health issue. METHODS: The present study was conducted in three teaching hospitals affiliated with Tehran University of Medical Sciences (Tehran, Iran) from Sep 2012 to Mar 2013. To study the relationship between metals and childhood growth, concentrations of zinc and several potentially toxic metals (lead, cadmium, antimony, cobalt, and molybdenum) were measured in scalp hair for 174 children, aged 20 to 36 months. RESULTS: The hair concentrations of cobalt were significantly (P<0.05) higher in children at the lower percentile of weight than in higher-weight children (0.026 ± 0.04 vs. 0.015 ± 0.01 µg/g, respectively). Hair contents of lead, cobalt, and antimony were significantly higher (P<0.05) in girls than in boys (8.08 ± 8.7 vs. 4.92 ± 5.6 µg/g for lead, 0.026 ± 0.03 vs. 0.16 ± 0.02 µg/g for cobalt, and 0.188 ± 0.29 vs. 0.102 ± 0.12 µg/g for antimony). There were also significant correlations between lead and other metals in the children's hair. CONCLUSION: Gender may play a significant role in absorption and/or accumulation of metals. It should be considered when we study metal toxicity in children.

Selective boron delivery by intra-arterial injection of BSH-WOW emulsion in hepatic cancer model for neutron capture therapy.

OBJECTIVE: Boron neutron-capture therapy (BNCT) has been used to inhibit the growth of various types of cancers. In this study, we developed a 10BSH-entrapped water-in-oil-in-water (WOW) emulsion, evaluated it as a selective boron carrier for the possible application of BNCT in hepatocellular carcinoma treatment. METHODS: We prepared the 10BSH-entrapped WOW emulsion using double emulsification technique and then evaluated the delivery efficacy by performing biodistribution experiment on VX-2 rabbit hepatic tumour model with comparison to iodized poppy-seed oil mix conventional emulsion. Neutron irradiation was carried out at Kyoto University Research Reactor with an average thermal neutron fluence of 5 × 1012 n cm-2. Morphological and pathological analyses were performed on Day 14 after neutron irradiation. RESULTS: Biodistribution results have revealed that 10B atoms delivery with WOW emulsion was superior compared with those using iodized poppy-seed oil conventional emulsion. There was no dissemination in abdomen or lung metastasis observed after neutron irradiation in the groups treated with 10BSH-entrapped WOW emulsion, whereas many tumour nodules were recognized in the liver, abdominal cavity, peritoneum and bilateral lobes of the lung in the non-injected group. CONCLUSION: Tumour growth suppression and cancer-cell-killing effect was observed from the morphological and pathological analyses of the 10BSH-entrapped WOW emulsion-injected group, indicating its feasibility to be applied as a novel intra-arterial boron carrier for BNCT. Advances in knowledge: The results of the current study have shown that entrapped 10BSH has the potential to increase the range of therapies available for hepatocellular carcinoma which is considered to be one of the most difficult tumours to cure.

In vivo evaluation of neutron capture therapy effectivity using calcium phosphate-based nanoparticles as Gd-DTPA delivery agent.

PURPOSE: A more immediate impact for therapeutic approaches of current clinical research efforts is of major interest, which might be obtained by developing a noninvasive radiation dose-escalation strategy, and neutron capture therapy represents one such novel approach. Furthermore, some recent researches on neutron capture therapy have focused on using gadolinium as an alternative or complementary for currently used boron, taking into account several advantages that gadolinium offers. Therefore, in this study, we carried out feasibility evaluation for both single and multiple injections of gadolinium-based MRI contrast agent incorporated in calcium phosphate nanoparticles as neutron capture therapy agent. METHODS: In vivo evaluation was performed on colon carcinoma Col-26 tumor-bearing mice irradiated at nuclear reactor facility of Kyoto University Research Reactor Institute with average neutron fluence of 1.8 × 10(12) n/cm(2). Antitumor effectivity was evaluated based on tumor growth suppression assessed until 27 days after neutron irradiation, followed by histopathological analysis on tumor slice. RESULTS: The experimental results showed that the tumor growth of irradiated mice injected beforehand with Gd-DTPA-incorporating calcium phosphate-based nanoparticles was suppressed up to four times higher compared to the non-treated group, supported by the results of histopathological analysis. CONCLUSION: The results of antitumor effectivity observed on tumor-bearing mice after neutron irradiation indicated possible effectivity of gadolinium-based neutron capture therapy treatment.

Evaluation of the metabolic chiral inversion of d-selenomethionine in rats by stable isotope dilution gas chromatography-mass spectrometry.

The stereoselective pharmacokinetics of selenomethionine enantiomers in rats has been studied to evaluate the chiral inversion of D-selenomethionine to the L-enantiomer. After bolus intravenous administration of D- or L-selenomethionine to rats, the plasma concentrations of these two enantiomers were determined by stereoselective gas chromatography-mass spectrometry with selected ion monitoring. This method involved derivatization of selenomethionine enantiomers with HCl in methanol to form methyl ester followed by N-acylation with (+)-α-methoxy-α-trifluoromethylphenylacetyl chloride to form the diastereomeric amide, and separation of the diastereomer on GC with an achiral column. Plasma concentrations of administered D- and L-selenomethionine declined with terminal half-lives of 96 ± 17 min and 91 ± 6 min, respectively. L-Selenomethionine appeared rapidly in plasma after administration of D-selenomethionine, whereas D-selenomethionine was not detected in plasma after administration of L-selenomethionine. The fraction of conversion of D-selenomethionine to L-selenomethionine was estimated to be 61.3 ± 14.5%. The present method evaluates the stereoselective pharmacokinetics of selenomethionine enantiomers, including the estimation of the metabolic chiral inversion.

The relation of maternal blood arsenic to anemia during pregnancy.

To clarify the relationship of prenatal arsenic exposure to hemoglobin concentrations and anemia during pregnancy, a longitudinal study was conducted of 364 participants during early pregnancy from October 2006 to March 2011 in Tehran, Iran. Maternal whole blood (taken between 8-12 and 20-24 weeks of gestation, and at delivery) and umbilical cord blood samples were collected for arsenic measurement. The mean concentration of maternal blood arsenic in the first trimester of pregnancy was significantly lower in anemic women compared with non-anemic participants (mean ± SD: 12.4 ± 3.4 versus 14.8 ± 4.0 µg/L, respectively, p < 0.001). Maternal whole blood arsenic levels in the first and third trimesters were significantly (p < 0.05) correlated with hemoglobin concentrations measured throughout gestation (r = 0.312, 0.424, and 0.183). Multiple logistic regression analysis demonstrated that increased maternal blood arsenic levels in the first trimester were significantly negatively associated to anemia during pregnancy (OR = 0.85, CI: 0.77-0.94, p < 0.01). The present study showed that prenatal blood arsenic exposure was not a risk factor for the occurrence of anemia.

Low level prenatal blood lead adversely affects early childhood mental development.

The effect of prenatal lead exposure on child development has been a topic of public health concern for decades. To estimate prenatal lead exposure effects on early childhood development, maternal blood (n = 364) and umbilical cord blood (n = 224) samples were collected during pregnancy and at delivery. Mental development was assessed using the Harold Ireton Early Child Development Inventory from 174 children. Maternal whole blood lead levels in the first trimester were significantly higher in children with developmental scores <20% than in those with normal scores (mean ± standard deviation: 6.3 ± 1.9 vs 4.0 ± 2.4 µg/dL, respectively, P = .01). Maternal blood lead levels in the first trimester were also inversely associated with the development scores (r = -0.155, P = .041). Logistic regression analysis showed a significant relationship between increasing maternal blood lead levels in the first trimester with low development scores (odds ratio = 1.74, 95% confidence interval = 1.18-2.57, P = .005). The findings of the present study showed a relatively low level of prenatal lead exposure (mean < 6.5 µg/dL) associated with lower developmental scores in early childhood.

Tumor growth suppression by gadolinium-neutron capture therapy using gadolinium-entrapped liposome as gadolinium delivery agent.

Neutron capture therapy (NCT) is a promising non-invasive cancer therapy approach and some recent NCT research has focused on using compounds containing gadolinium as an alternative to currently used boron-10 considering several advantages that gadolinium offers compared to those of boron. In this study, we evaluated gadolinium-entrapped liposome compound as neutron capture therapy agent by in vivo experiment on colon-26 tumor-bearing mice. Gadolinium compound were injected intravenously via tail vein and allowed to accumulate into tumor site. Tumor samples were taken for quantitative analysis by ICP-MS at 2, 12, and 24 h after gadolinium compound injection. Highest gadolinium concentration was observed at about 2 h after gadolinium compound injection with an average of 40.3 µg/g of wet tumor tissue. We performed neutron irradiation at JRR-4 reactor facility of Japan Atomic Energy Research Institute in Tokaimura with average neutron fluence of 2×10¹² n/cm². The experimental results showed that the tumor growth suppression of gadolinium-injected irradiated group was revealed until about four times higher compared to the control group, and no significant weight loss were observed after treatment suggesting low systemic toxicity of this compound. The gadolinium-entrapped liposome will become one of the candidates for Gd delivery system on NCT.

Selenium metabolism and excretion in mice after injection of (82)Se-enriched selenomethionine.

The organic Se compounds (particularly selenomethionine [SeMet]) in plants and yeasts are very effective chemoprotectants for mammalian cancer. To characterize the dynamics of selenomethionine utilization pathways, we intravenously injected (82)Se-enriched SeMet into mice under different nutritional states (Se-adequate and Se-deficient mice) and then measured their endogenous and exogenous (82)Se levels. Furthermore, we quantified Se compounds and selenoproteins in liver, kidneys, plasma, and urine. The average recoveries of exogenous (82)Se from solid tissues, urine, and feces were 81% for Se-adequate mice and 84% for Se-deficient mice. Exogenous (82)Se was distributed in the hepatic and renal cytosols as cellular glutathione peroxidase (cGPx), selenosugar, and SeMet within 1 h after injection. Synthesis of cGPx was maintained until 72 h after injection, regardless of the Se nutritional status. Whereas plasma levels of exogenous (82)Se as selenoprotein P (Sel-P) peaked at 6 h after injection, those of Se-containing albumin (SeAlb), extracellular GPx, and SeMet peaked at 1 h after injection. These results suggest three Se transport pathways in mice injected with SeMet: SeAlb (within 1 h after injection); SeMet (from 1 to 72 h after injection); and Sel-P (from 6 to 72 h after injection). The amount of Sel-P in Se-deficient mice was 1.5 times that of Se-adequate mice, and this increase was much larger than Se-containing compounds other than Sel-P. Our results indicate that Sel-P has an important role in Se transport when the nutritional supply of Se is insufficient.

Long-term oral lithium treatment attenuates motor disturbance in tauopathy model mice: implications of autophagy promotion.

Lithium, a drug used to treat bipolar disorders, has a variety of neuroprotective mechanisms including inhibition of glycogen synthase kinase-3 (GSK-3), a major tau kinase. Recently, it has been shown that, in various neurodegenerative proteinopathies, lithium could induce autophagy. To analyze how lithium is therapeutically beneficial in tauopathies, transgenic mice overexpressing human mutant tau (P301L) were treated with oral lithium chloride (LiCl) for 4 months starting at the age of 5 months. At first, we examined the effects of treatment on behavior (using a battery of behavioral tests), tau phosphorylation (by biochemical assays), and number of neurofibrillary tangles (NFTs) (by immunohistopathology). In comparison with control mice, LiCl-treated mice showed a significantly better score in the sensory motor tasks, as well as decreases in tau phosphorylation, soluble tau level, and number of NFTs. Next, we examined lithium effects on autophagy using an antibody against microtubule-associated protein 1 light chain 3 (LC3) as an autophagosome marker. The number of LC3-positive autophagosome-like puncta was increased in neurons of LiCl-treated mice. Neurons containing NFTs were completely LC3-negative, whereas LC3-positive autophagosome-like puncta contained phosphorylated-tau (p-tau). The protein level of p62 was decreased in LiCl-treated mice. These data suggested that oral long-term lithium treatment could attenuate p-tau-induced motor disturbance not only by inhibiting GSK-3 but also by enhancing autophagy in tauopathy model mice.

Feasibility evaluation of neutron capture therapy for hepatocellular carcinoma using selective enhancement of boron accumulation in tumour with intra-arterial administration of boron-entrapped water-in-oil-in-water emulsion.

INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the most difficult to cure with surgery, chemotherapy, or other combinational therapies. In the treatment of HCC, only 30% patients can be operated due to complication of liver cirrhosis or multiple intrahepatic tumours. Tumour cell destruction in boron neutron-capture therapy (BNCT) is due to the nuclear reaction between (10)B atoms and thermal neutrons, so it is necessary to accumulate a sufficient quantity of (10)B atoms in tumour cells for effective tumour cell destruction by BNCT. Water-in-oil-in-water (WOW) emulsion has been used as the carrier of anti-cancer agents on intra-arterial injections in clinical. In this study, we prepared (10)BSH entrapped WOW emulsion by double emulsifying technique using iodized poppy-seed oil (IPSO), (10)BSH and surfactant, for selective intra-arterial infusion to HCC, and performed simulations of the irradiation in order to calculate the dose delivered to the patients. MATERIALS AND METHODS: WOW emulsion was administrated with intra-arterial injections via proper hepatic artery on VX-2 rabbit hepatic tumour models. We simulated the irradiation of epithermal neutron and calculated the dose delivered to the tissues with JAEA computational dosimetry system (JCDS) at JRR4 reactor of Japan Atomic Research Institute, using the CT scans of a HCC patient. RESULTS AND DISCUSSIONS: The (10)B concentrations in VX-2 tumour obtained by delivery with WOW emulsion were superior to those by conventional IPSO mix emulsion. According to the rabbit model, the boron concentrations (ppm) in tumour, normal liver tissue, and blood are 61.7, 4.3, and 0.1, respectively. The results of the simulations show that normal liver biologically weighted dose is restricted to 4.9 Gy-Eq (CBE; liver tumour: 2.5, normal liver: 0.94); the maximum, minimum, and mean tumour weighted dose are 43.1, 7.3, and 21.8 Gy-Eq, respectively, in 40 min irradiation. In this study, we show that (10)B entrapped WOW emulsion could be applied to novel intra-arterial boron delivery carrier for BNCT, and we show the possibility to apply BNCT to HCC. We can irradiate tumours as selectively and safety as possible, reducing the effects on neighbouring healthy tissues.

Simultaneous determination of selenomethionine enantiomers in biological fluids by stable isotope dilution gas chromatography-mass spectrometry.

A method for the stereoselective determination of D- and L-enantiomers of selenomethionine in mouse plasma was developed using gas chromatography-mass spectrometry with selected-ion monitoring (GC-MS-SIM). DL-[(2)H(3,)(82)Se]selenomethionine was used as analytical internal standard to account for losses associated with the extraction, derivatization and chromatography. Selenomethionine enantiomers in mouse plasma were purified by cation-exchange chromatography using BondElut SCX cartridge and derivatized with HCl in methanol to form methyl ester followed by subsequent N-acylation with optically active (+)-α-methoxy-α-trifluoromethylphenylacetyl chloride to form diastereomeric amide. Quantification was performed by SIM of the molecular-related ions of the diastereomers on the chemical ionization mode. The intra- and inter-day precision for D- and L-selenomethionine spiked to mouse plasma gave good reproducibility with relative standard deviation of 3% and 3% for D-selenomethionine and 6% and 3% for L-selenomethionine, respectively. The estimated amounts were in good agreement with the actual amounts spiked, the intra- and inter-day relative error being 5% and 2% for D-selenomethionine and 2% and 1% for L-selenomethionine, respectively. The present method is sensitive enough to determine pharmacokinetics of selenomethionine enantiomers.

Tumor accumulation of ε-poly-lysines-based polyamines conjugated with boron clusters.

Boron Neutron Capture Therapy (BNCT) is one of the potent cancer radiotherapies using nuclear reaction between (10)B atoms and the neutron. Whether BNCT will succeed or not depends on tumor selective delivery of (10)B compounds. ε-Poly-L-lysine is a naturally occurring polyamine characterized by the peptide linkages between the carboxyl and ε-amino groups of L-lysine. Because of high safety ε-PLL is applied practically as a food additive due to its strong antimicrobial activity. In this study, we focus on a development of a novel polymeric delivery system for BNCT using biodegradable ε-PLL conjugated with (10)B-containing clusters (BSH). This polymeric boron carrier will be expected to deliver safely and efficiently into tumor tissues based on Enhanced Permeability and Retention (EPR) effect.

Chronic magnesium deficiency decreases tolerance to hypoxia/reoxygenation injury in mouse heart.

AIMS: Magnesium (Mg) deficiency has been reported to be associated with the development of the metabolic syndrome, cardiovascular diseases, and sudden death. We examined the influence of chronic Mg deficiency on cardiac tolerance to hypoxia/reoxygenation injury. MAIN METHODS: Mice were fed an Mg-deficient diet for 4 weeks, and then their hearts were excised for Langendorff perfusion experiments. The levels of total Mg in the blood and heart were quantified by atomic absorption spectrometry. KEY FINDINGS: In Mg-deficient mice, the Mg concentration in whole blood was markedly decreased; however, that in the heart remained unchanged. When the hearts of control mice were exposed to hypoxia/reoxygenation, removal of extracellular Mg from a normal Krebs solution containing 1.2 mM Mg resulted in a significant decrease in the recovery of the tension-rate product (TRP) upon reoxygenation. In Mg-deficient mice, the recovery of TRP in the heart was reduced significantly in the absence of extracellular Mg compared to that in controls. The addition of Mg to the perfusate did not improve TRP recovery. During hypoxia/reoxygenation, cardiac damage evaluated by myocardial aspartate amino transferase (AST) release was greater in hearts of Mg-deficient mice than in that of control mice. SIGNIFICANCE: These results indicate that chronic Mg deficiency causes severe hypomagnesemia and a decrease in cardiac tolerance to hypoxia, without changing the intracellular Mg content. The decreased tolerance to hypoxia was not affected by the presence or absence of extracellular Mg, suggesting that some intracellular metabolic abnormalities develop in the cardiac myocytes of Mg-deficient mice.

Blood lead at currently acceptable levels may cause preterm labour.

OBJECTIVES: Although occupational and environmental exposures to lead have been dramatically reduced in recent decades, adverse pregnancy outcomes have been observed at 'acceptable' levels of blood lead concentrations (≤ 10 µg/dl). METHODOLOGY: Blood samples were collected from 348 singleton pregnant women, aged 16-35 years, during the first trimester of pregnancy (8-12 weeks) for lead measurement by inductively coupled plasma-mass spectrometry. Subjects were followed up and divided into two groups (preterm and full-term deliveries) according to duration of gestation. RESULTS: The average (range) and geometric means of blood lead levels were 3.8 (1.0-20.5) and 3.5 µg/dl, respectively. Blood lead level was significantly (p<0.05) higher in mothers who delivered preterm babies than in those who delivered full-term babies (mean±SD: 4.46±1.86 and 3.43±1.22 µg/dl, respectively). Logistic regression analysis demonstrated that a 1 unit increase in blood lead levels led to an increased risk of preterm birth (OR 1.41, 95% CI 1.08 to 1.84). CONCLUSION: Adverse pregnancy outcomes may occur at blood lead concentrations below the current acceptable level.

Synthesis of D- and L-selenomethionine double-labeled with deuterium and selenium-82.

The synthesis of D- and L-selenomethionine labeled with 8²Se and three deuteriums at Se-methyl group (D- and L-[²H3, 8²Se]selenomethionine) was described. D- And L-[²H3, 8²Se]selenomethionine were prepared by condensation of (R)- and (S)-2-amino-4-bromobutylic acid with lithium [²H3, 8²Se]methaneselenolate, which was prepared from metal (82)Se and [²H3]methyl iodide. The optical purities of D- and L-[²H3, 8²Se]selenomethionine were determined by HPLC with a chiral stationary phase column and were found more than 99% ee. The chemical ionization mass spectra showed that the molecular related ion for N-isobutyloxycarbonyl ethyl ester derivatives of [²H3, 8²Se]selenomethionine did not overlap with the m/z values known from that of non-labeled selenomethionine.

Dynamic pathways of selenium metabolism and excretion in mice under different selenium nutritional statuses.

The selenoprotein, cellular glutathione peroxidase (cGPx), has an important role in protecting organisms from oxidative damage through reducing levels of harmful peroxides. The liver and kidney in particular, have important roles in selenium (Se) metabolism and Se is excreted predominantly in urine and feces. In order to characterize the dynamics of these pathways we have measured the time-dependent changes in the quantities of hepatic, renal, urinary, and fecal Se species in mice fed Se-adequate and Se-deficient diets after injection of (82)Se-enriched selenite. Exogenous (82)Se was transformed to cGPx in both the liver and kidney within 1 h after injection and the synthesis of cGPx decreased 1 to 6 h and continued at a constant level from 6 to 72 h after injection. The total amount of Se associated with cGPx in mice fed Se-deficient diets was found to be less than in mice fed Se-adequate diets. This finding indicated that cGPx synthesis was suppressed under Se-deficient conditions and did not recover with selenite injection. Excess Se was associated with selenosugar in liver and transported to the kidney within 1 h after injection, and then excreted in urine and feces within 6 h after injection. Any excess amount of Se was excreted mainly as a selenosugar in urine.