Crit Rev Clin Lab Sci 1989;27(6):483-541

Selenium: clinical significance and analytical concepts.

Lockitch G

Department of Pathology, British Columbia's Children's Hospital, Vancouver,

Canada.

Selenium is an essential trace element in humans and animals. Its only established function in humans is the antioxidant activity of glutathione peroxidase, a selenoenzyme. Severe prolonged deficiency may cause a fatal cardiomyopathy. Iatrogenic causes of selenium deficiency include parenteral and enteral nutrition. Low plasma selenium is also found in malabsorption, cystic fibrosis, rheumatoid arthritis, neoplasia, and other varied clinical disorders. Death has resulted from a single massive ingestion of selenium, while chronic excessive intake causes skin, nail, and hair pathology. Extreme geographical variation in population blood and urine selenium levels and a marked age-specific variation in population reference intervals are important factors in understanding selenium nutrition. Nutritional requirements, biological availability, and metabolism are discussed in relation to geographical, age, and method variability. Sampling, processing procedures, and methods for selenium quantitation are reviewed. Selenium content in different biological matrices and reference values for pediatric, adult, and obstetric populations are provided.

PMID: 2690856, UI: 90104564

Eur J Pediatr 1984 Apr;142(1):21-4

Blood selenium content and glutathione peroxidase activity in children with cystic fibrosis, coeliac disease, asthma, and epilepsy.

Ward KP, Arthur JR, Russell G, Aggett PJ

Long-term selenium status in children from the North-East of Scotland was estimated using whole blood selenium content (BSe) and glutathione peroxidase activity (BGSH-Px). BSe was significantly lower than the reference range in children with cystic fibrosis, coeliac disease and in older patients with phenylketonuria. Whereas BGSH-Px of all the children with coeliac disease and those with cystic fibrosis aged over 6 years matched the reference range, it was reduced in younger patients with cystic fibrosis and in children with dietetically treated phenylketonuria. No child had clinical features of selenium deficiency. BSe in treated epileptics and asthmatics conformed to the reference range, but BGSH-Px in both groups was increased significantly; this was most evident in those receiving corticosteroid preparations.

PMID: 6714254, UI: 84182636

Acta Paediatr Scand 1983 May;72(3):437-40

Plasma and erythrocyte zinc, copper and selenium in cystic fibrosis.

Neve J, Van Geffel R, Hanocq M, Molle L

Plasma and erythrocyte zinc, copper and selenium were measured in 20 cystic fibrosis children, aged 7 to 19 years. Mean plasma zinc and copper levels were not different from those in age-matched controls but very low zinc levels occurred sporadically. Plasma zinc concentrations were significantly lower in patients with moderate-to-severe growth retardation and with severe pulmonary disease as compared to patients without growth failure and with moderate pulmonary disease. Mean erythrocyte zinc (40.8 micrograms/g Hb +/- 9.2) and copper levels (3.56 micrograms/g Hb +/- 0.50) were very significantly increased (30.4 micrograms/g Hb +/- 5.2 and 2.73 micrograms/g Hb +/- 0.30 respectively, for age-matched controls). Mean plasma and erythrocyte selenium levels (63 ng/ml +/- 15 and 329 ng/g Hb +/- 86) were significantly lower than those in age-matched controls (82 ng/ml +/- 13 and 404 ng/g Hb +/- 116). The trace element concentrations in erythrocytes are discussed in relation to the activities of the copper- and zinc-containing enzyme superoxide dismutase and the seleno-enzyme glutathione peroxidase. We consider that more data on trace element metabolism in CF should be collected before specific supplementation is considered.

PMID: 6880733, UI: 83278933

Pediatrics 1980 May;65(5):1010-2

Selenium and glutathione peroxidase levels in cystic fibrosis.

Lloyd-Still JD, Ganther HE

Whole blood selenium and glutathione peroxidase levels were measured in 20 infants and children (aged 6 months to 15 years) with cystic fibrosis. The whole blood selenium concentration in cystic fibrosis was 0.122 +/- 0.025 microgram/gm. Although the levels of selenium in cystic fibrosis children were below the levels found in a study of healthy children (0.223 +/- 0.007 microgram/gm), they are comparable to those found in children with phenylketonuria treated dietetically and exceed the blood selenium level of healthy children in New Zealand. Levels of the selenoenzyme glutathione peroxidase in children with cystic fibrosis (0.042 +/- 0.007 units/mg Hb) were in the normal range (0.035 +/- 0.003 units/mg of Hb). These results do not support the hypothesis that deficiency of selenium is reponsible for cystic fibrosis.

PMID: 7367113, UI: 80166631

Pediatr Res 1975 Dec;9(12):885-8

Serum glutathione reductase and cystic fibrosis.

Shapiro BL, Smith QT, Warick WJ

Serum glutathione reductase (NADPH-GSSG oxidoreductase, EC. 1.6.4.2 (GR)) as been examined in cystic fibrosis subjects (CF), obligate CF heterozygotes, and control subjects. Serum protein concentration was similar in the three groups. Regardless of the units used to express activity (milligrams of protein or milliters of serum) or whether or not samples were dialyzed against water or phosphate buffer, mean serum GR in CF was greater than in control subjects (P less than or equal to 0.002) in all series over several years. Under the above assay conditions no difference in serum GR between control subjects and carriers was detected. Calculated and assayed values of combined control and CF sera agreed as did expected and observed 50% activity in 1:2 sera dilutions in CF, control subjects, and carriers. Addition of FAD to incubation media did not effect enzyme activity in the three groups. Differences between CF and control subjects persisted after dialysis in membranes permitting passage of molecules of approximately 12,000 mol wt or less. These findings would tend to exclude the effect of extraneous serum factors in explaining the diffferences between CF and control subjects. The percentage of initial GR activity after four days storage (0-4 degrees) was significantly greater in CF than in control subjects (P less than 0.025). The effect of heparin on serum GR was recorded as the percentage of activity after incubation with heparin vs. activity in the standard assay for individual subjects. The effect of incubation with 5 mug/ml heparin on serum GR activity was greater in control subjects than in carriers (P less than 0.0005) and CF (P less than 0.0005). Mean serum GR activity in CF and carriers was unaffected by heparin, whereas mean activity in control subjects was decreased. In no control was the percentage of initial activity with heparin greater than the mean of CF and carrier groups. Only 3 of 20 CF and 4 of 20 carrier individuals had percentages lower than the control mean. The CF and carrier distributions were clearly different from the control distribution. Serum GR was determined in seven non-CF individuals with chronic obstructive pulmonary disease (COPD). Activity in the COPD was different from CF and no different from control subjects. In none of these controls or COPD was serum GR as great as the CF mean. Serum GR in no CF was as low as the mean of control subjects or COPD. It is concluded that serum GR activity is greater in CF than in control subjects, carriers, and non-CF COPD subjects; that the difference in activity is not attributable to an extraneous serum factor, that the activity difference is not secondary to chronic respiratory disease; that in comparison with control subjects, GR from CF serum behaves differently after storage; and that serum GR from CF and carriers behaves differently from control GR in the presence of heparin.

PMID: 1196705, UI: 76076866

Toxicology 1989 Oct 16;58(3):249-66

Dose-related effects of enzyme-generated oxidants on the biochemistry and morphology of the hamster lung.

Nakashima JM, Hyde DM, Giri SN

Department of Veterinary Pharmacology and Toxicology, School of Veterinary

Medicine, University of California, Davis 95616.

Reactive oxygen species (ROS) have been closely associated with a number of pathological disorders, including interstitial pulmonary fibrosis. While models of ROS-induced fibrosis offer advantages over chemically-induced fibrosis, the biochemical and morphological features of ROS-induced fibrosis have yet to be extensively documented. In this study, we evaluated the effect of initial ROS dose on lung injury and repair. Male hamsters received a single dose of glucose, glucose oxidase and lactoperoxidase via the intratracheal route. From 3 to 14 days post-treatment, a significant dose-related body weight loss was observed. There was a trend towards greater mortality with increasing dose. After 2 weeks, we noted significant, dose-related increases in lung levels of collagen, lipid peroxidation products, nucleic acids, and protein. Similarly, total lung catalase, lactic dehydrogenase and glutathione reductase activities were also elevated significantly above control values in a dose-related fashion. A concurrent, dose-dependent thickening of alveolar septa in ROS-treated lungs was composed of epithelial hyperplasia, hyperemia, edema and accumulations of interstitial fibers and macrophages. Interstitial and alveolar macrophages in ROS-induced lesions were enlarged and contained numerous primary and secondary lysosomes. These results demonstrate that, in the hamster lung, injury induced by enzyme-generated ROS can initiate dose-dependent fibroproliferative changes which eventuate into interstitial fibrosis.

PMID: 2678604, UI: 90020291

Am Rev Respir Dis 1989 Feb;139(2):370-2

Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis.

Cantin AM, Hubbard RC, Crystal RG

Pulmonary Branch, National Heart, Lung and Blood Institute, Bethesda, Maryland

20892.

Glutathione (L-gamma-glutamyl-L-cysteinyl-glycine, GSH), a sulfhydryl-containing tripeptide produced by most mammalian cells, is an efficient scavenger of toxic oxidants, including hydrogen peroxide, an oxidant that plays a major role in the oxidant burden placed on the epithelial surface of the lower respiratory tract in chronic inflammatory states. GSH is present in the epithelial lining fluid of the normal lower respiratory tract, where it is thought to play a major role in providing antioxidant protection to the epithelial cells. In this regard, we hypothesized that the lower respiratory tract of patients with IPF may be chronically depleted of this antioxidant, thus leading to an increased susceptibility of lung epithelial cells to oxidant injury. To evaluate this concept, the concentration of glutathione was determined in the epithelial lining fluid of the lower respiratory tract of 15 patients with IPF and compared to that of 19 normal subjects. Strikingly, whereas ELF glutathione concentrations were high in normal subjects (429 +/- 34 microM), a fourfold decrease was found in patients with IPF (97 +/- 18 microM, p less than 0.001). In the context of the known oxidant burden present in the lower respiratory tract of patients with IPF, these observations of a "GSH deficiency" in IPF ELF suggest that there is a marked oxidant-antioxidant imbalance at the alveolar surface of these persons, thus increasing the susceptibility to the severe epithelial cell damage characteristic of this disease.

PMID: 2913886, UI: 89116672

Exp Mol Pathol 1988 Oct;49(2):254-66

Effects of buthionine sulfoximine on the development of ozone-induced pulmonary fibrosis.

Sun JD, Pickrell JA, Harkema JR, McLaughlin SI, Hahn FF, Henderson RF

Lovelace Biomedical and Environmental Research Institute, Albuquerque, New

Mexico 87185.

The capacity of reduced glutathione (GSH) to protect lung tissue against ozone-induced pulmonary fibrosis was investigated. Male B6C3F1 mice were exposed to 0, 0.2, 0.5, and 1.0 ppm ozone for 23 hr/day for 14 days. During exposures and/or for a period of 90 days after exposures, subgroups of mice at each exposure level were given drinking water containing 30 mM L-buthionine-S,R-sulfoximine (BSO) to lower in vivo levels of GSH. These BSO treatments reduced blood glutamylcysteine synthetase (GCS) activity (regulatory enzyme for GSH biosynthesis) and lung nonprotein sulfhydryl (NPSH) levels in nonexposed animals by approximately half. In contrast, ozone exposures increased blood GCS activity and lung NPSH levels in a concentration-dependent manner, with smaller increases in the BSO-treated mice. Immediately after exposures, an ozone-related inflammatory response was seen in lungs, but no histopathological signs of developing fibrosis were evident. Ninety days later, mice exposed to 1 ppm ozone and not treated with BSO had modest evidence of pulmonary fibrosis. Mice exposed to 1 ppm ozone and treated with BSO during this post-exposure period (regardless of BSO treatment during exposures) showed histopathological evidence of exacerbated pulmonary fibrosis, compared to similarly exposed mice not treated with BSO postexposure. These results indicated that interference with the body's normal defense mechanisms against oxidant damage, including suppression of GSH biosynthesis, exacerbates the subsequent development of pulmonary fibrosis.

PMID: 2901982, UI: 89005547

Free Radic Biol Med 1988;4(6):399-402

Oxygen metabolite detoxifying enzyme levels in bleomycin-induced fibrotic lungs.

Fantone JC, Phan SH

Department of Pathology, University of Michigan Medical School, Ann Arbor

48109-0602.

The activities of three enzymes cytosolic superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSHP), and malonyldialdehyde (MDA), a by-product of lipid peroxidation, were determined in whole lungs of normal and bleomycin-treated rats. Two days after bleomycin treatment total lung SOD, CAT, and GSHP activities were significantly (p less than .025) depressed between 15 and 25%. The activities of all three enzymes increased 4 days after bleomycin treatment with only SOD significantly increased at days 4 and 7. Total lung CAT activity remained near normal levels while GSHP activity increased only at day 28 (160.5%, p less than .01) indicating a specificity of the response of lung SOD and GSHP levels. Total lung MDA levels were increased by 17% at 2 and 4 days (p less than .05) after bleomycin treatment, and returned to normal levels at 7 and 28 days. These data suggest that impairment of the lung's ability to detoxify O2 metabolites may play an important role in the development of bleomycin-induced pulmonary fibrosis.

PMID: 2454874, UI: 88255905

Chest 1986 Mar;89(3 Suppl):111S-113S

Accumulation of lung tissue oxidized glutathione (GSSG) as a marker of oxidant induced lung injury.

White CW, Mimmack RF, Repine JE

PMID: 3948571, UI: 86134920

Fundam Appl Toxicol 1984 Oct;4(5):760-7

Enhanced oxygen toxicity following treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea.

Kehrer JP, Paraidathathu T

The anticancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) inhibits glutathione reductase, an enzyme involved in oxidant defense systems. The 30-day LD50 for BCNU in male and female BALB/c mice was 52 and 46 mg/kg, respectively. A 35-mg/kg BCNU dose was not lethal to any animal. Glutathione reductase was inhibited in lung tissue by about 50% for 4 days following a single 35 mg/kg dose of BCNU. The prolonged inhibition of glutathione reductase by BCNU suggested this drug might enhance pulmonary oxygen toxicity by diminishing the lung's antioxidant capacity. Exposing mice treated with 35 or 50 mg/kg BCNU to continuous 85% oxygen decreased the LT50 from 13.1 to 6.3 and 5.3 days, respectively, compared to vehicle-treated controls. All mice treated with 35 mg/kg BCNU or vehicle and exposed to 85% oxygen only on Days 0-4 survived to Day 30. Extending the hyperoxic exposure 1 additional day resulted in the death of all BCNU-treated mice, while 70% of the vehicle-treated mice survived to Day 30. Pulmonary glutathione peroxidase, catalase, and superoxide dismutase activities were unaffected up to 6 days following 35 mg/kg BCNU, 85% oxygen, or both. Pulmonary glutathione reductase activity was unaffected by 85% oxygen alone, although hyperoxia extended the BCNU-induced inhibition of this enzyme to Day 6. BCNU, 35 mg/kg, had little effect on lung reduced glutathione (GSH) levels. A significant decrease was only measured on Day 4. Hyperoxia, either alone or with BCNU, had no effect on lung GSH content.

PMID: 6510607, UI: 85077355