Selenium ByAnne

in Rheumatic

Diseases

M. Peretz, Jean D. Nhve, and Jean Pierre P. Famaey

Selenium is involved in several important biochemical pathways relevant to rheumatic diseases. Experimental and clinical studies suggest that selenium modulates the inflammatory and immune responses. Patients suffering from inflammatory rheumatic diseases often have low selenium levels, but this finding does not correlate with disease severity. Selenium supplementation needs stricter selection criteria and better

T

HE ROLE of selenium as an essential nutrient has been extensively studied since the early 1980s. Deficiency of this element is associated with defined clinical symptoms in animals and humans.’ Most recent data support a protective role of selenium against diseases characterized by free radical injury, such as the adult respiratory distress syndrome,‘.’ emphysema,” atherosclerosis,’ ischemic cerebral disease,’ cancer,” and arthritis.’ This property is due mainly to the involvement of selenium in the enzyme glutathione peroxidase, active in the detoxification of free radicals and other damaging oxygen derivatives. The first study that emphasized the role of selenium in the etiopathogenesis of rheumatic diseases was published by Roberts in 1963. While screening natural compounds for antitumoral activity, he discovered antiinflammatory properties of an inorganic derivative isolated from a liver fraction, identified as selenium.‘.’ Ten years later, Berenstein demonstrated the effect of selenium supplementation on the antibody production of rabbits.“’ Since then, much work has been carried out in vitro and in vivo to clarify the role of selenium in inflammatory and immune responses. The aim of this review is to summarize knowledge of this trace element relevant to rheumatic diseases. stressing data from in vitro and experimental animal models for possible clinical applications in humans. Two subjects will be more particularly considered: (1) the physiopathological implications of selenium related to free radicals, the inflammatory response (phagocytic cells, arachidonic acid metabolism), and the immune response; (2) in vivo animal and human studies. Semmars m Arthr&s andRheumatism,

ascertainment of dose to obtain a stimulatory or inhibitory effect relevant to the disease state. Prevention of marginal selenium deficiency by moderate supplementation might enhance host defense mechanisms. Copyright c 1991 by W.B. Saunders Company INDEX WORDS: selenium; inflammation; immunity. PHYSIOLOGICAL

rheumatic

diseases;

EFFECTS OF SELENIUM

Role of Oxygen-Derived Free Radicals In rheumatoid arthritis (RA), the destructive properties of the synovial pannus are among others attributed to an abnormal production of phlogistic agents including proteolytic enzymes, and oxygen-derived free radicals (ODFRs).” ” Experimental data on the ability of synovial fluid to produce superoxide (0, ) and hydroxyl (OH’) radicals clearly demonstrate that both species are directly responsible for the depolymerization of hyaluronic acid.“’ In vitro studies further demonstrate the degradation of intact human cartilage,” proteoglycans,‘” and collagen” by ODFRs. The characterization in synovial fluid of high levels of malondialdehyde, a well known by-product of lipid peroxidation, is additional evidence of oxidative damage.lY Although protective mechanisms exist in the synovial fluid against proinflammatory products,“‘.“’ they appear insufficient when deleterious species are produced in large quantities as in RA.

From the Depurtment of‘Rheumatoloa and Physx al Medicine, Saint-Pierre Hospital and the Lahoruto? ofPharmaceutical Chemistry Institute of Pharmacy, E‘rw Uniwr.sity of Brussels. Belgium. Supported by the Nationul Fund for Scwntifk Medical Research, Belgium (grant FRSM no. 3-4.510-87). Anne M. Peretz. MD: Department of RheumatoloK) and Physical Medicine, Saint-Pierre Hospital: Jean D. N&e. PhD: Laboratory of Pharmaceutical Chemistq. hzstitute of Pharmacy, Free University of Brussels: Jean Pierre P. Famaey, MD, PhD: Department of Rheumato@q and Phwical Medicine, Saint-Pierre Hospital. Address reprint requests to Anne Peretz. MD, Deparwwnt of Rheumatology and Ph.vsical Medicine, Samt-Pierre Hospital, rue Haute 322, B-1000 Brussels, Belgium. Copyright c 1991 by W.B. Saunder.s C’ompam 0049.0172191i2005-OOO4$5.OOlO

Vol 20, No 5 (April), 1991: pp 305.316

305

306

PERETZ, N&E,

Indeed, activity of physiological antioxidants like superoxide disrnutase, catalase, glutathione peroxidase, and ceruloplasmin are reduced in rheumatic diseases.2’m23 Oxygen free radical production also affects autoimmune processes.24 There is good evidence that these species attack several biomolecules creating new antigens. For example, exposure to an O,-’ generating system modifies the desoxyribonucleic acid to compounds with antigenie activity responsible for the production of antinuclear factors.25 Lunec et aI*’ suggested that free radical generation in RA is responsible for the production of altered immunoglobulin G (IgG) giving rise to rheumatoid factor that subsequently may become a stimulus for neutrophils to generate radicals.” This last mechanism is consistent with the self-perpetuation of free radical release and tissue degradation observed in RA.

AND FAMAEY

activation that generates ODFRs (O,-, OH’), peroxides, singlet oxygen, and hypochlorite anions that are responsible for oxygen-dependent killing of microorganisms.” These reactions likely are harmful in pathological conditions when inappropriate activation of cells occurs, such as in RA, or when regulatory mechanisms are deficient. The physiological factors responsible for turning off these pathways are not completely characterized; however, some evidence exists that selenium is one of these factors. As a constituent of the active site of the enzyme glutathione peroxidase, the element is involved in the intracellular detoxification of H,O,, produced by the dismutation of 02- into molecular oxygen (0,) by the cytosolic enzyme, superoxide dismutase (Fig 1). Selenium is also involved in the production of NADP’ by the glutathione peroxidase/glutathione reductase system that finally activates the hexose monophosphate shunt.29,“’ Accumulation of H,02 within the cell catalyzes the production of the toxic OH’ radical (through the Haber-Weiss and Fenton reactions) and decreases the production of NADP’. These events ultimately cause dam-

Selenium and the Inflammatory Response: Phagocytic Cells and the Arachidonic Acid Cascade

The “respiratory burst” occuring in the inflamed joint space is related to neutrophil IMMUNE RESPONSE

PEROXIDES

INFLAMMATION -

FREE RAD1ChLS SUPEROXIDE ANION

M Detoxification

ARACHIDONIC ACID

\

v

METABOLISM

Se

PROSTAGLANDINS 4

LEUKOTRIENES

GSH-Px Synthesis

killing Fig 1: Oxygen system and selenium involvement (GSH-Px, glutathione peroxidase).

SELENIUM AND RHEUMATIC

307

DISEASES

age to biomembranes and other cellular structures. In favor of the importance of selenium in this action, selenium deficiency impaired some phagocytic cell functions while, selenium supplementation completely corrected the defect.” Peritoneal macrophages from rats fed a selenium-deficient diet exhibit increased H,O, production,” and granulocytes from seleniumdeficient animals are unable to metabolize H,O, leading to the destruction of their 02-’ generating system.33~is These in vitro investigations are supported by in vivo studies performed mostly in animals but also in humans. Increased susceptibility to infection was observed in selenium-deficient animals. Impairment of the fungicidal activity in selenium-deficient rats”’ and cattle”’ is frequently reported, but modifications in bactericidal activity and phagocytosis are not unanimously recognized.“‘.‘h~ig Decreased chemotaxis in selenium-deficient rats4” and goats” are corrected with selenium supplementation.“’ The disturbances are explained in part by the low glutathione peroxidase content of the cells and in part by other peroxidase-independent mechanisms.j’ In humans, the addition of selenium to cultures of neutrophils from healthy subjects enhanced bactericidal activity.4’ Effective doses were 1.27 and 2.53 Fmol/L, corresponding to serum concentrations considered adequate for platelet glutathione peroxidase activity.“” However, supplementation trials in Finish subjects failed to demonstrate such an effect.“s In addition to its role in the detoxification of peroxides during the activation of phagocytic cells. selenium also is involved in the biosynthetic pathway of proinflammatory prostaglandins (PG) and leucotrienes (LT) (Fig 2).” The element participates in several steps of both the cyclooxygenase and lipoxygenase pathways of the arachidonic acid cascade through the activity of glutathione peroxidase but also via other enzymatic functions (Fig 3). It modulates the production of PGE,,47 thromboxane A, and PGI,4x.“’ in the cycloxygenase pathway. In the lipoxygenase pathway, glutathione peroxidase mediates the reduction of 12-hydroperoxyeicosatetraenoic acid (12-HPETE) to 12-hydroxyeicosatetraenoic acid (12-HETE).‘” Platelets from selenium-deficient rats produce more trihydroxyeicosatetraenoic acid (THETE) and less 12HETE than platelets from control rats, indicat-

ing that THETE is an alternate pathway when the peroxidase-mediated conversion of 12HPETE is impaired. The conversion of 5-HPETE to the inactive metabolite, 5-HETE, in leukocytes is also mediated by glutathione peroxidase. Selenium supplementation alters the synthesis of LTs to 5-HETE, while selenium deficiency promotes the synthesis of LTA, and derived LTs.” Other authors argue, on the contrary, that selenium promotes the synthesis of LTs.” Indirect evidence for this comes from the study on pulmonary alveolar macrophages of selenium-deficient rats that produce less LTB4. Some investigators even suggest that glutathione peroxidase activity should be inhibited rather than enhanced in inflammatory diseases.” Despite these conflicting data, it is presently agreed that selenium and glutathione peroxidase play a significant role in PGs and LTs biosynthesis. Hence, selenium possesses antiinflammatory properties by virtue of its role in the detoxification of peroxides, in the conversion of 5-HPETE into 5-HETE, as well as proinflammatory properties via the stimulation of PGEz and perhaps LTB, biosynthesis. To determine their relative importance, further in vivo investigations are required.

Selenium and the Immune Response T and especially B lymphocytes are very sensitive to the “peroxide tone” of their microenvironment.s4 Small amounts of H,Oz stimulate lymphocyte reactivity while larger amounts have damaging effects.5r The lymphocyte functions are altered by peroxide attack of the cell membrane receptors as well as of various intracellular structures such as microtubules and microfilaments. Indeed, the lymphocyte proliferating response to mitogens and antigens requires the presence of cell surface thiol groups in their active reduced forms.56 This state depends on several factors, such as the peroxide level, the intracellular glutathione pool, and the amount of inorganic metabolites of selenium (HZSe) present in the cell.“-“’ Selenium therefore contributes to the maintenance of the cell integrity both as a constituent of glutathione peroxidase and as inorganic selenium (Fig 4). Several studies in RA indirectly support these data: a low glutathione pool was reported in red blood cells and in serum”.“; plasma sulfhydryl levels

308

PERETZ, Nk’E,

PHAGOCYTIC

AND FAMAEY

CELLS

RESPIRATORY

BURST

GLUCOSE CONSUMPTION

NADPH oxidase

glucose oxidase Glut-

NADPH

:p-yRib-

NADP

5P NADPH

NADPH'

Fig 2:

H2°2

+

H2°2

+

Involvement

02:

--OH'

Fe2+ -OH'

of selenium

and glutathione

+ OH-

+ 0

+ OH-

+ Fe 3+(Fenton)

peroxidase

2

(Haber-Weiss)

(GSH-Px)

in inflammation.

Relations

between the different pathways.

also were reduced.63 Similar data were obtained in rat adjuvant arthritis.64 Selenium deficiency is associated with a reduced animal survival rate after challenge with potentially lethal microorganisms,‘j5 and vaccination of selenium-deficient animals is not followed by immunization.6h On the other hand, selenium supplementation enhances the synthesis of specific antibodies against bacteria, fungi, and sheep red blood cells.67-69Selenium deficiency reduces the ability of T and B cells to proliferate in response to stimulation with various mitogens and antigens,‘03’l while selenium supplementation increases their responses.” Selenium deficiency impairs the leukocyte migration inhibitory factor production without modification of interleukin 1 and II production.73 The addition of sodium selenite in cultured human

lymphocytes enhances the production of interferon.75 Some of these data were recently confirmed by two in vivo studies in humans demonstrating enhancement of cell-mediated immune response by selenium supplementation in elderly subjects and in patients requiring total parenteral nutrition (TPN).75.76 It is noteworthy that selenium affects both humoral and cell-mediated immune responses in a dose-dependent manner: low doses are immunostimulant, whereas high doses are immunosuppresive. For example, low to moderate selenium concentrations (0.75 to 1.75 ppm) in the diet of mice stimulate the antibody synthesis6’while high doses (5 ppm) have an inhibitory effect.” Use was made of both properties in clinical practice. High selenium doses from 400 to 800 kg/d served as adjuvant therapy in the

SELENIUM AND RHEUMATIC

309

DISEASES

Hz02

FREE RADICALS

CELL MEMBRANE L

J PHOSPHOLIPASE A2

LYPOOXYGE;~/

CYCLOOXYGENASE

"PETE

PGG2

Platelets

1

CSH_;;)HpEy(;'qyy

IZHETE

THETE

S jq\

SHETE

LTA4

Se

Fig 3: involvement of selenium and glutathione peroxidase

in the metab-

olism of arachidonic acid.

treatment of gynecological or gastrointestinal cancers while moderate ones, 200 to 300 kgid, were advised for cancer prevention.” Enhancement of the lymphocyte response to mitogens

H,SeO,

GSH Transferase

/v LTB4 LTC&

PGF24

TXA2

PGE:, PGD2 PROSTAGLANDINS

PGI2 PROSTACYCLIN

i TXB2 THROMBOXANE

LTDL LTE4

and antigens was obtained at lower “nutritional” doses, ie, 100 to 200 kg/d in elderly and TPN patients.75.76 In preliminary studies, acquired immunodeficiency syndrome (AIDS) patients

Fig 4: Role of selenium in immunocompetent cells.

310

PERETZ, NEW, AND FAMAEY

were supplemented with selenium to stimulate their failing immunity but the results were not convincing.“~” In addition to dose, the duration of intervention and the chemical form of selenium supplementation also influence its activity. On the basis of the previously mentioned in vitro studies, inorganic selenium salts (selenite) appears more effective than organic derivatives. However, selenomethionine or selenium-enriched yeast usually are prefered in clinical trials because of better bioavailability. Although no effect could be demonstrated in healthy subjects given SeIenomethionine (200 kg/d for 3 months),45 a stimulation of NK cells” and of T lymphocyte response to mitogens”.” was reported using sodium selenite,80 selenomethionyeast” at similar ine,76 or selenium-enriched doses for 2 to 6 months. The immunomodulatory properties of selenium are most likely mediated by the activity of glutathione peroxidase and depend on the dose and the form administered. However, as discussed, some effects are related to the functions of other selenoproteins or products of selenium metabolism that are not fully identified. CLINICAL STUDIES

Animals The discovery that selenium possessed antiinflammatory properties prompted Roberts” to assess several selenium compounds at various doses in the treatment of experimental inflammation. The reduction of exudate in the rat granuloma pouch assay was best when treated with sodium selenite. The antiinflammatory effect obtained after intraperitoneal administration of selenite was maximum for doses ranging from 4 to 14 l&kg body weight. Similarly, sodium selenite improved the survival of lupus mice, but no modification in immunologic parameters was noted.” In rats receiving a selenium-deficient diet, worsening of the late phase of adjuvant arthritis was reported in one study3’ but not confirmed in another.” A study of selenium status in the progression of adjuvant arthritis in rats showed that plasma and liver selenium concentrations decreased only in the late phase of the disease. The levels did not correlate with clinical and biochemical indices of inflammation and probably are the conse-

quence of the chronic, tory status.”

nonspecific,

inflamma-

Humans The antiinflammatory and immunomodulatory properties of selenium prompted studies in RA, juvenile rheumatoid arthritis (JRA) and other types of arthritis. Most studies were performed in Europe, especially in Scandinavia, where the selenium status of the entire population is low, at least until selenium was added to soil fertilizers in 1984.’ In most studies of RA patients, plasma selenium was significantly lower than healthy controls (Table I). The largest reductions were found in Norway (1.19 v 1.64 pmol/L) and France (0.60 v 0.91 ~mol/L).x’~xy The only nonEuropean author reported similar levels in RA and controls.‘” Tarp et al”@ established a significant correlation between plasma selenium concentrations and various clinical indices of disease severity, but not with the classical biochemical indices of inflammation. Other investigatorSX4-X6.XY could not correlate plasma selenium levels with these clinical indices. Selenium concentrations rarely were measured in other body compartments although such studies would give additional information on the status and distribution of the element. Erythrocyte selenium was assessed in only three studies; low” or normaP values were reported. Using a sophisticated technique, the microprobe assay, Lindh and Johanson” were unable to detect selenium in erythrocytes, granulocytes, and platelets of RA patients, but their method was very insensitive. In RA, synovial membraney2 and synovial fluid” selenium concentrations were increased when compared with those from osteoarthritis. Selenium accumulates within the articular space, probably as a result of both increased permeability of the inflamed synovial membrane and extracellular release from damaged leukocytes and synoviocytes. Measurement of glutathione peroxidase activity was another approach to evaluate the selenium status of these patients. Low,‘~ normap,x9,94-9h and even increased9’ erythrocyte activities of this enzyme were reported. Results of selenoenzyme activity, in the absence of simultaneous assessment of plasma selenium concentration, may lead to misinterpretation,

SELENIUM AND RHEUMATIC

311

DISEASES

Table 1: Plasma Selenium in RA Patients and Controls From Several Countries

I

Authors

Country

Controls

RAW)

References

Munthe (1978)

Norway

1.19 " 0.32 (23)

1.64 f 0.25 (23)

83

Sullivan(1979)

USA

1.51 ? 0.37 (10)

1.51 + 0.12 (37)

90

Mottonen(1984)

Finland

0.95 5 0.12 (20)

1.13(0.89-1.50)

89

Akesson*(1984)

Sweden

0.82 2 0.20 (26)

1.00 f 0.16 (28)

101

Makela* (1984)

Finland

1.01 5 0.14(57)

0.94 ? 0.12

102

Aaseth (1985)

Norway

1.19 5 0.32(23)

1.53 -c0.25 (40)

84 107

1.10(0.65-1.81)(29)

Almroth (1985) Tarp(1985)

Denmark

0.80 (0.72-0.93)(6)

1.07 (0.91-1.40)(6)

87

Makela" (1987)

Finland

0.69(0.53-0.88)(125)

0.88(0.56-1.211657)

103

Peretz(1987)

Belgium

0.97 ? 0.25(45)

1.06 i 0.18 (45)

86

Arnaud (1988)

France

0.60 2 0.28 (20)

0.91 -t0.28 (20)

85

Borglund (1988)

Sweden

0.84 ? 0.11 (7)

0.98 * 0.03 (5)

Honkanen*(1989)

Finland

0.69 t 0.09(125)

0.82 + 0.12 (657)

Tarp(1989)

Denmark

0.91 2 0.19 (24)

1.01 ? 013(127)

95 104 88

*In JRA patients. Note Results are expressedin pmol/L, mean t SD or range, (N).

particularly as selenium supplementation is becoming more popular in Western countries.” In addition, erythrocyte glutathione peroxidase is a poor index of marginal selenium deficiency and short-term alterations of selenium status.“” Plasma or platelet glutathione peroxidase arc more sensitive, but not easily measurable for clinical purposes.““’ In JRA, decreased plasma selenium is reported frequently and correlates with disease duration.““~“” Low erythrocyte glutathione peroxidase activity in these children favors selenium deficiency.“” JRA patients seem, therefort, more prone to develop selenium deficiency than adult rheumatoid patients. Insufficient selenium body store, one possible explanation, is supported by the observation of lower selenium levels in healthy children than in healthy adults living in the same area.“” Osteoarthritis patients had similar plasma selenium and erythrocyte glutathione peroxidasc as age- and sex-matched controls in a Belgian study,“” but lower than normal erythrocytc glutathione peroxidase was reported in a Swedish study.“‘” Plasma selenium in systemic lupus erythematosus patients was in the normal range although a trend to lower values was observed in active disease.“” The selection of patients probably biases the data as plasma zinc concentrations were also normal rather than low. as usually observed in patients suffering from an inflammatory disease.‘“’ In HLA B27

positive patients with inflammatory findings, an attempt to relate abnormal chemotaxis to the selenium status was unsuccessfuI.“‘x Reduced glutathione peroxidase activity also was reported in other connective tissue diseases, but unfortunately selenium concentrations were not measured simultaneously.“‘” From these studies it may be concluded that modifications in selenium status. when present, are not directly related to the inflammatory process. However, even in the absence of pronounced selenium deficiency. it might be useful to determine whether these patients would benefit from selenium supplementation to prevent or correct the damaging effects of the oxidative stress of inflammation. Selenium as a Therapeutic Agent Most selenium supplementation trials were performed with organic selenium compounds with or without vitamin E. RA patients supplemented with selenium-enriched yeast (Selena, Leiras Pharmaceuticals, Turku, Finland, 256 pg of selenium per day) for 6 months did not improve their health status even when their deficient selenium status was corrected.““Simultaneously, granulocyte glutathione peroxidase increased during supplementation but never reached normal values. According to the authors, this might explain the lack of clinical and biological improvement.“’ Supplementation with sodium selenite (160 kg of selenium per day)

312

PERETZ, NCVE, AND FAMAEY

for 4 months,83 selenomethionine (100 l_rg/d),112 or selenium-enriched yeast (200 ug/d) (Peretz et al, personal data, 1989-1990) improved approximately 40% of a small group of RA patients. Finally, a selenium supplementation trial (Selenium ACE, Wassen Intl, Leatherhead, England, 100 kg/d) in osteoarthritic patients produced no improvement in the patient’s health status.113Some weaknesses in this protocol include (1) osteoarthritis patients are not good candidates for selenium supplementation as this is a degenerative disease without clear evidence of inflammatory process or immune impairment, (2) selenium status before and after supplementation was not evaluated. Selenium supplementation should not be undertaken in severe disease or after the failure of more powerful therapeutic agents, Selenium probably acts rather physiologically by stimulation of preexisting defense mechanisms, and therefore differs largely from classical antirheumatic drugs. Ebselen (Cologne, Germany) (2-phenyl-1,2 benzisoselenazol-3(2H)-one) is a seleno-organic compound with antiinflammatory activities. Its activity through catalytic reduction of peroxides in the presence of thiols is similar to that of endogenous glutathione peroxidase.“4-“h It is weakly active in classical models such as rat carrageenan paw edema and adjuvant arthritis and more active in cobra venom factor paw edema and the glucose oxidase monoarthritis models.“’ A recent attempt was made to select potentially active drugs in the benzisoselenazolone series of Ebselen analogs. One of these

compounds, RP61605, has shown promise as a possible new antiinflammatory compound.“x Effect of Drug Treatment on Selenium Status D-Penicillamine as a structural analog of the aminoacid cysteine, possesses a thiol group able to form mixed disulfide bounds with sulfur containing proteins. This drug might protect the cell surface thiol groups of immunocompetent cells against free radical damage and increase the reduced glutathione pool within the cell making the glutathione peroxidaseireductase system more effective.1’9,12”On the other hand, D-penicillamine inhibits glutathione peroxidase activity in the same way as other thiol-containing compounds that have also been assessed in RA treatment such as thiopyridoxine, thiopropionylglycine, tiopronine, or captopril. Discordant properties of D-penicillamine were thus reported in relation to selenium metabolism: the antioxidant and immunomodulatory effects via the protection of thiol groups contrasts with the inhibitory effect on glutathione peroxidase. Gold compounds also are strong and reversible inhibitors of glutathione peroxidase. The binding site for gold is the aminoacid selenocysteine on the active site of the enzyme.‘*‘~“* In vitro and in vivo experiments in rats showed a redistribution of selenium among tissues and subcellular compartments after administration of aurothioglucose (gold I), aurothiomalate and auranofin because of the formation of goldselenium complexes.“’ These forms decrease the availability of selenium for the biosynthesis of glutathione peroxidase.

Table 2: Selenium (Se) Levels and Inflammatory Variables in Patients With RA Treated With Various Corticosteroid Doses Prednisolone, mgfd Variable

7.5

20

60

Number of patients

7

7

5

Plasma-Se, pmol/L

1.17 ? 0.20

0.88 k 0.20*

0.55 r 0.15*

Erythrocyte-Se,

4.76 5 1.14

4.67 2 1.39

5.00 ?T0.95

7.4 + 1.7

7.4 k 2.9

8.00 k 2.9

72 (42-l 20)

49 (10-100)

nmol/g Hb

Erythrocyte glutathione peroxidase, ,U/g Hb ESR, mm/h

*P < ,025, Student’st-test. Abbreviations: Hb, hemoglobin: ESR, erythrocyte sedimentation rate. Note. Results are expressed as mean + SD or range. Adapted with permission.”

49 (30-60)

SELENIUM AND RHEUMATIC

313

DISEASES

Finally corticosteroids, drugs that affect macromineral metabolism (eg, sodium, potassium, and calcium) can also influence trace elements, such as zinc”“.“’ and selenium. Corticosteroids lowered plasma selenium levels without modify-

ing erythrocyte glutathione peroxidase activity.‘” As indicated in Table 2, the effect was dose dependent. Its action could not be attributed to alterations of plasma-carrier proteins or urinary selenium excretion.“”

REFERENCES 1. Neve .I, Vertongen F, Molle L: Selenium deficiency. Clin Endocrinol Metab 14:629-656,198s 2. Hammond B, Kontos HA, Hess ML: Oxygen radicals in the adult respiratory distress syndrome, in myocardial ischemia perfusion injury, and in cerebral vascular damage. Can .I Physiol Pharmacol63:173-187, 1985 3. Sweder van Asbeck B, Hoidal J, Vercellotti GM, et al: Protection against lethal hyperoxia by tracheal insufflation of erythrocytes: Role of red cell glutathione. Science 227:756757,198s 4. Pryor WA: Free radicals in cigarete smoke, in Mittman C, Taylol JC, Church DF (eds): Pulmonary Emphysema and Proteolyses. (Vol2). New York, NY, Academic Press, 1987 5. Barrowcliffe TW, Gray E, Kerry PJ, et al: Lipid peroxidases. lipoproteins, and thrombosis. Life Chem Rep 3:174-188. 1985 6. Moody CS, Hassan HM: Mutagenecity of oxygen free radicals. Proc Nat1 Acad Sci 79:2855-2859,1982 7. Torrielli MV, Dianzani MV: Free radicals in inflammatory diseases, in Amstrong D, Sohal RS, Culter RG, et al (eds): Free Radicals in Molecular Biology, Aging and Disease. New York, NY; Raven Press, 1984, pp 355-379 8. Roberts ME: Antiinflammation studies 1. Antiinflammatory properties of liver fractions. Toxicol Appl Pharmaco1 5:485-488, 1963 Y. Roberts ME: Antiinflammation studies. II. Antiinflammatory properties of selenium. Toxicol Appl Pharmacol 5:500-506, 1963 IO. Berenstein TF: Effect of selenium and vitamin E on antibody formation in rabbits. Zdrawookhr Beloruss 18:3441. 1972 Il. Harris E: Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med 322:1277-89, 1990 12. Muirden KD: Lysosomal enzymes in synovial membrane in rheumatoid arthritis. Relationship with joint damage. Ann Rheum Dis 31:365-372,1972 13. Bragt PC, Ransberg JI, Bonta IL: Antiinflammatory effects of free radical scavengers and antioxidants. Inflammation 4:289-299. 1980 14. Greenwald RA, Moy WW: Effect of oxygen-derived free radicals on hyaluronic acid. Arthritis Rheum 23:455463, 1980 15. Burkhardt H, Schwingel M, Menniger H, et al: Oxygen radicals as effecters of cartilage destruction. Arthritis Rheum 29:379-3887, 1986 16. Greenwald RA, Moy WW, Mainardi C: Degradation of cartilage proteoglycans and collagen by superoxide radical. Arthritis Rheum 19:799, 1976 (abstr) 17. Monboisse JC, Braquet P, Randoux A, et al: Non enzymatic degradation of soluble calf skin collagen by superoxide ion: Protective effect of flavonoids. Biochem Pharmacol 3253-58, 1983

18. Wade CR, Jackson PG, Highton J. et al: Lipid peroxidation and malondialdehyde in the synovial fluid and plasma of patients with rheumatoid arthritis. Clrn Chem Acta 164:245-250, 1987 19. Biemond P, Swaak G, Koster J: Protective factors against oxygen free radicals and hydrogen peroxide in rheumatoid arthritis synovial fluid. Arthritis Rheum 27:760765,1984 20. McCord JM: Free radicals and inflammation: Protection of synovial fluid by superoxide dismutase. Science 1X5:529-531, 1974 21. Schalkwitk J, Vandenberg WB, Levinus AB, et al: Cationization of catalase, peroxidase and superoxide dismutase. J Clin Invest 17:138-205, 1985 22. Blake DR. Hall ND. Treby DA, et al: Protection against superoxide and hydrogen peroxide in synovial fluid from rheumatoid patients. Clin Sci 61:483-486. 1985 23. Gutteridge JMC, Winyard PG, Blake DR, et al: The behaviour of caeruloplasmin in stored extracellular fluids in relation to ferroxidase II activity, lipid peroxidation and phenanthroline detectable copper. Biochem J 230517.523, 1985 24. Halliwell B: Production of superoxide. hydrogen peroxide and hydroxyl radicals by phagocytic cells: A cause of chronic inflammatory disease. Cell Biol Int Rep 6:520541, 1982. 25. Jansson G: Formation of antibodies to native DNA in rats after administration of native DNA treated with the xanthine-xanthine oxidase system. Free Radical Res Commun 1985 26. Lunec J, Halloran SP, White AC. et al: Free radical oxidation (peroxidation) products in serum and synovial fluid in rheumatoid arthritis. J Rheumatol8:233-245. 1981 27. Lunec J: Fluorescence: A marker of free-radical damage induce in human gamma-globulin. Biochem Sot Trans 10:21-26,1982 28. Babior M: Oxygen-dependent microbial killing by phagocytes. N Engl J Med 289:659-668, 1978 29. Bryant RW, Simon TC, Bailey JM: Role of glutathione peroxidase and monophosphate shunt in the platelet lipoxygenase pathway. J Biol Chem 257:14937-14943, 1982 30. Tschesche H, MacCartney HW: A new principal of regulation of enzyme activity activation and regulation of human polymorphonuclear leucocyte collagenase via disulfide-thiol exchange as catalysed by the glutathione cycle in a peroxide coupled reaction to glucose metabolism, Eur J Biochem 120:83-90, 1981 31. Aziz ES, Kleisus PH, Frandsen JC: Etfects of selenium on polymorphonuclear leukocyte function in goats. Am J Vet Res 45:1715-1718, 1984 32. Parnham MJ. Winkelmann JL. Leyck S: Macrophage,

314

lymphocyte and chronic inflammatory responses in seleniumdeficient rodents. Association with decreased glutathione peroxidase activity. Int J Immunopharmacol5:455-461,1983 33. Baker S, Cohen HJ: Altered oxidative metabolism in selenium deficient rat granulocytes. J Immunol 130:28562860,1983 34. Dimitrov NV, Ulrey DE, Primack S, et al: Selenium as a metabolic modulator of phagocytosis, in Combs GE, Spallholz JE, Levander OA, et al (eds): Selenium in Biology and Medicine. New York, NY, AVI Publishing, 1985, pp 254-262 35. Baker SS, Cohen HJ: Increased sensitivity to H,O, in glutathione-peroxidase deficient rat granulocytes. J Nutr 114:2003-2009,1984 36. Serfass RE, Ganther HE: Defective microbial activity in glutathione peroxidase-deficient neutrophils of selenium deficient rats. Nature 255:640-641, 1985 37. Boyne R, Arthur JR: Alterations of neutrophil function in selenium deficient cattle. J Comp Path01 91:271-276, 1979 38. Gyang ED, Stevens JB, Olson WG, et al: Effects of selenium-vitamin E injection on bovine polymorphonucleated leukocytes, phagocytosis and killing of staphylococcus aureus. Am J Vet Res 45:17.5-177,1984 39. Bass DA, Dechatelet LR, Burth RFet al: Polymorphonuclear leukocyte bacterial activity and oxidative metabolism during glutathione peroxidase deficiency. Infect Immuno1 18:78-84,1977 40. Basford RE, Sartus B, Kaplan SS et al: Glutathione peroxidase and phagocytosis, in Rossi S, Patriarca P, Romeo D (eds): Movement, Metabolism and Bactericidal Mechanism of Phagocytosis. New York, NY, Piccin Medical, 1977, pp 263-275 41. McCallister J, Harris RE, Baehner PL, et al: Alteration of microtubule function in glutathione peroxidase deficient polymorphonuclear leukocytes. J Reticuloend Sot 25:59-66, 1980 42. Aziz ES, Klesius PH: Depressed neutrophil chemotactic stimuli in supernatant in ionophore-treated polymorphonuclear leukocytes from selenium-deficient goats. Am J Vet Res 47:140-152, 1986 43. Urban T, Jarstrand C: Selenium effects on human neutrophilic granulocyte function in vitro. Immunopharmacology 12:167-172, 1986 44. Nke J, Vertongen F, Cape1 P: Selenium supplementation in healthy belgian adults: Response in platelet glutathione peroxidase activity and other blood parameters. Am J Clin Nutr 48:139-144, 1988 45. Arvillomi H, Poikonen K, Jokinen I, et al: Selenium and immune functions in humans. Infect Immunity 41:185189,1983 46. Lands WEN: Biological consequences of fatty acid oxygenase reaction mechanisms. Prostagland Leukotr Med 13:35-46, 1984 47. Schoene NW: Selenium-dependent glutathione peroxidase and eicosanoid production, in Lands WEN (ed): Biochemistry of Arachidonic Acid Metabolism. Boston, MA, Martinus Nijhoff, 1985, pp 151-160 48. Bryant RW, Bailey JM: Altered lipoxygenase metabolism and decreased glutathione peroxidase activity in

PERETZ, NbE,

AND FAMAEY

platelets from selenium deficient rats. Biochem Biophys Res Comm 92126.276,198O 49. Toivanen JL: Effects of selenium, vitamin E and vitamin C on human prostacyclin and thromboxane synthesis in vitro. Prostagland Leukotr Med 26:265-280, 1987 50. Doni MG, Bonaccorso EP: High glutathione peroxidase and prostacyclin-like activity generation in rat aorta. Haemostasis 13:248-253,1983 51. McCarty M: Can dietary selenium reduce leukotriene production? Med Hypotheses 13:45-50, 1984 52. Gairola C, Tai HH: Selective inhibition of leukotriene by biosynthesis in rat pulmonar alveolar macrophages by dietary selenium deficiency. Biochem Biophys Res Comm 132:397-401, 1985 53. Dillard LJ, Baker MA, Gavin0 VC, et al: Effect of dietary selenium and injected gold thioglucose on adjuvanttreated rats. Drug Nutr Inter 3:153-163, 1985 54. Farber CM, Liebes LF, Kanganis DN, et al: Human B lymphocytes show greater susceptibility to H202 toxicity than T lymphocytes. J Immunol 132:2453-2456, 1984 55. Novogrodsky A, Ravid A, Rubin AZ, et al: Hydroxyl radical scavengers inhibit lymphocyte mitogenesis. Proc Nat1 Acad Sci 79:1171-1174, 1982 56. Noelle RJ, Lawrence DA: Determination of glutathione in lymphocytes and possible association of redox state and proliferative capacity of lymphocytes. Biochem J 198:571-579, 1981 57. Meister A, Andersen ME: Glutathione. Ann Rev Biochem 52:71 I-760, 1983 58. Peretz A: Selenium in inflammation and immunity, in Nhe J, Favier A (eds): Selenium in Medicine and Biology. Berlin, Germany, Waiter De Gruyter, 1989 59. Kiremidjian-Schumacher L, Stotzky G: Selenium and immune responses. Environ Res 42:277-303,1987 60. Gasiewicz TA, Smith JC: The metabolism of selenite by intact rat erythrocytes in vitro. Chem Biol Interact 21:299-313, 1978 61. Munthe E, Kass E, Jellum E: D-Penicillamineinduced increase in intracellular glutathione correlating to clinical response in rheumatoid arthritis. J Rheumatol 8:14-19, 1981 62. Banford JC, Brown DH, Hazelton RA, et al: Altered thiol status in patients with rheumatoid arthritis. Rheumato1 Int 2:107-l 1, 1982 63. Hall ND, Blake DR, Bacon PA: Serum sulfhydtyl levels in early synovitis. J Rheumatol9:593-596, 1982 64. Baumgartner WA, Beck FWJ, Lorber A, et al: Adjuvant disease in rats: biochemical criteria for distinguishing several phases of inflammation in arthritis. Proc Sot Exp Biol Med 165:625-630, 1974 65. Boyne R, Mann SO, Arthur JR: Effect of salmonella tiphymurium infection on selenium deficient rats. Microbial Lett 27:83-87, 1984 66. Murray, JM, Murray AB: The effects of selenium deficiency and repletion on host resistance to infection, in Mills CE, Bremmer I, Chester JK (eds): Trace Element Metabolism in Man and Animals. Cambridge UK, Commonwealth on Agricultural Bureaux, 1985, pp 244-247 67. Spallholtz JE: Selenium: what role in immunity and immune cytotoxicity? in Spallholtz JE, Martin JL, Ganther

SELENIUM AND RHEUMATIC

DISEASES

315

HE (eds): Selenium in Biology and Medicine. Westport, CT. AVI. 1981, 103-117 6X. Keller LD, Exon JH, Talkott P, et al: Immune responses in rats supplemented with selenium. Clin Exp lmmunol 63570-576, 1986 69. Mulhern SA, Taylor GL, Magruder LE, et al: Deticient level of dietary selenium suppresses the antibody response in first and second generation mice. Nutr Res ‘:201-220, 1985 70. Reffett JK. Spears JW, Talmage T, et al: Effects of dietary selenium on the primary and secondary immune response in calces challenged with infections bovine rhinotracheitis virus. J Nutr 18X:229-235, 1988 71. Eskew ML. Scholr RW, Reddy CC, et al: Effects of vitamin E and selenium deficiencies on rat immune function. Immunology 54:173-1X0, 1985 72. Turner RJ, Wheatley LB, Beck NEG: Stimulatory effects of selenium on mitogen response in lambs. Vet lmmunol Immunopathol X:1 19-124, 1985 73. Aziz ES. Klesius PH: The effect of selenium deficiency in goats on lymphocyte production of leukocyte production of leukocyte migration inhibitory factor. Vet lmmunol Immunopathol 10:3X1-390, 1986 74. Watson RR, Moriguchi S, McRae B. et al: Effects of selenium in vitro on human T lymphocyte functions and K-562 tumor cell growth. J Leuk Biol39:447-457, 19X6 75. Per&z A, N&e J. Duchateau J, et al: Enhancement of lymphocyte response to mitogens by supplementation of elderly subjects with selenium-enriched yeast. Am J Clin Nutr 199 1, in press. 76. Peretz A, NPve J. Duchateau J. et al: Effects of selenium supplementation on immune parameters in patients on total parenteral nutrition. Nutrition 1991, in press. 77. Schrauzer GN: Selenium and cancer; Historical developments and perspectives, in Spallholtz JE, Martin JL, Ganther HE (eds): Selenium in Biology and Medicine. Westport. CT. AVI Publishing, 19X1, pp 9X-102 7X. Dworkin BM, Rosenthal WS. Wormser GP, et al: Abnormalities of blood selenium and glutathione peroxidase activity in patients with acquired immunodeficiency syndrome and aids-related complex. Biol Trace El Res 15:167-177, 198X 74. Zarzo JB. Lafont A, Chappuis P. et al: Is non obstructive myocardiopathy (NOMC) in aids seleniumdeficiency-related. in N&e J. Favier A (eds): Selenium in Biology and Medicine. Berlin, Germany, Walter De Gruyter. 198’)

creased serum selenium in rheumatoid arthritis and in alcoholic cirrhosis, in Martin JL, Ganther HE, Spallholtz JE. (eds): Selenium in Medicine and Biology. Westport CT. Avi Publishing, 1981, pp 103-117 X5. Arnaud J, Zagala A, Imbaul-Huart V. et al: Selenium and other trace elements in patients with rheumatoid arthritis, in N&e J. Favier A (eds): Selenium in Medicine and Biology. Berlin, Germany. W de Gruyter, 198’1 X6. Peretz A. N&e J, Vertongen F, et al: Selenium status in relation to clinical variables and corticosteroid treatment in rheumatoid arthritis. J Rheumatol 14: 1104-l 107, 1987 X7. Tarp V, Overvad K, Hansen JC, et al: Low selenium in severe rheumatoid arthritis. Stand J Rheumatol 14:Y7101,1985 XX. Tarp U, Graudal H, Overvad K. et al: Selenium in Rheumatoid arthritis. A historical prospective approach. J Trace Elem Health Dis 3:93-96. 1989 X9. Mtittiinen T, Hannonnen P, Sepp&i 0. et al: Glutathione and selenium in rheumatoid arthritis. Clin Rheumatol 2: 195-200, lY84 90. Sullivan JF. Blotcky AJ, Jetton MM, el al: Serum levels of selenium, calcium, copper. magnesium. manganese and zinc in various human diseases. J Nutr 109: 1432.1437, 1979 91. Lindh U. Johanson E: The microelement profile in individual blood cells following selenium supplementation and in certain diseases. A nuclear microprobe application. Neurotoxicology 3:l-Il. 1983 92. McConnell KP. Broghamer WL.. Blotcky AJ, et al: Selenium levels in humans blood and tissues in health and disease. J Nutr 105:1026-1031, 1975 93. Per&z A. N&e J, Vertongen F, et al: Synovial fluid copper. zinc and selenium in relation to inflammatory parameters, in Sorenson JRJ (ed): Biology of Copper Complexes. Clifton. Humana Press. 1987. 583.5XU 94. Sonne M. Helleberg L, Jensen PT: Selenium status in patients with rheumatoid arthritis. Stand J Rheumatol 14:31x-319, 1985 Y5. Borglund M, Akesson A, Akesson B. et al: Distrihution of selenium and glutathione peroxidaae in plasma compared in healthy subjects and rheumatoid arthritis patients. Stand J Clin Invest 4X:27-32, IYXX 96. Abella A. Clerc D, Chalas J. et al: Concentration en superoxyde dismutase (cuivre et manganese). cat&se et glutathion peroxydase dans les hCmaties. le\ plaquettes et le plasma de sujets atteints de polyarthrite rhumatoidc. Ann Biol Clin 45:152-155, I987

X0. Dimitrov NV. Charamella IJ, Meyer CL. et al: Modulation of natural killer cell activity by selenium in humans. J Nutr Growth Cancer 3:193-19X. 1986 XI. O’Dell JR. McGivern JP, Kay HD; et al: Improved survival in murine lupus as the result of selenium supplementation. Clin Exp Immunol 7322-327, 1988 X2. N&e J. Fontaine J. Peretz A, et al: Changes in zinc, copper and selenium status during adjuvant-induced arthritl in rats. Agents Actions 25:146-155, 1988 X3. Munthe E, Aaseth J. Jellun E: Trace elements and rheumatoid arthritis (RA)-Pathogenic and therapeutic aspects. Acta Pharmacol Toxicol 59:365-373. 1986 X-l. Aaseth J. Thomassen Y, Alexander J. et al: Dc-

Y7. Braven J. Ansari N. Figgit P. et al: A comparison of glutathione reductase and glutathione peroxidase activities in patients with rheumatoid arthritis and healthy ddults. Br J Rheumatol28:212-215, 1989 YX. Tarp U: Selenium glutathione peroxidase in rheumatoid arthritis. Br J Rheumatol30:158, l9YO 99. Neve J: Biological parameters for assessing selenium status. in N&e J. Favier A (eds): Selenium in Medicine and Biology. Berlin. Germany. Walter de Gruyter. 1989, pp 137.148 100. N&e J. Chamart S. Van Erum S, et al: Selenium in humans as investigated by the effects of supplementation with Se-enriched yeast tablets, in N&e J, Favier A (eds):

316

Selenium in Medicine and Biology. Berlin, Germany, Walter de Gruyter, 1989, pp 315321 101. Akesson B, Johanson U, Ockerman PA: Selenium status in patients with juvenile chronic arthritis, in Bratter P, Schramel P (eds): Trace Element Analytical Chemistry in Medicine and Biology, (Vol3). Berlin, Germany, Walter De Gruyter, 1984, pp 167-174 102. Makela AL, HyorP H, Vuorinen K, et al: Trace elements (Fe, Zn, Cu and Se) in serum of rheumatic children living in western Finland. Stand J Rheumatol 53194, 1984 103. Makela AL, Tasanne M, Lazowska E: Selenium levels and glutathione peroxidase activities in erythrocytes of rheumatic and diabetic children and their families living in western Finland, in Bratter P, Schramel P (eds): Trace Element Analytical Chemistry in Medicine and Biology, (Vol 4). Berlin, Germany, Walter De Gruyter, 1987, pp 551-563 104. Honkanen V, Pelkonen P, Mussalo-Rauhamaa H, et al: Serum trace elements in juvenile chronic arthritis. Clin Rheumatol8:64-70, 1989 105. Peretz A, Ntve J, Famaey JP: Zinc, copper and selenium in chronic and acute inflammatory rheumatic diseases, in Bratter P, Schramel P (eds): Trace Element Analytical Chemistry in Medicine and Biology, (Vol 5). Berlin, Germany, W de Gruyter, 1988, pp 471-476 106. Bruce A: Swedish views on selenium. Ann Clin Res 18:8-12, 1986 107. Almroth G, Westberg NG, Sandstrom BM: Normal zinc and selenium levels in patients with systemic lupus erythematosus. J Rheumatol 12:633-634, 1985 108. Marklund SL, Repo H, Hoskimies S: Superoxide dismutase isoenzymes, glutathione peroxidase and selenium in blood from HLA B27-positive and negative subjects. Acta Path Microb Immunol Stand 95:107-111, 1987 109. Juhlin L, Edqvist LE, Ekman LG: Blood glutathione peroxydase in skin diseases: Effect of selenium and vitamin E treatment. Acta Dermatovener 62:211-214, 1982 110. Tarp V, Overvad K, Thorling E, et al: Selenium treatment in rheumatoid arthritis. Stand J Rheumatol 4:364-368,1985 111. Tarp V, Hansen JC, Overvad K, et al: Glutathione peroxidase activity in patients with rheumatoid arthritis and in normal subjects: Effects of long-term selenium supplementation. Arthritis Rheum 30:1162-1166, 1987 112. Meltzer HM, Myskja A: Selenium supplementation

PERETZ, NiVE,

AND FAMAEY

to rheumatics. Who responds? in: Proceedings of the Nordic Symposium: Metabolism of trace element related to human disease. Loen (Norway), 1985,36 (abstr) 113. Hill J, Bird HA: Failure of selenium ACE to improve osteoarthritis. Br J Rheumatol29:211-213,199O 114. Mulier A, Cadenas E, Graf P, Sies H: A novel biologically active seleno-organic compound. I. Glutathione peroxidase-like activity in vitro and antioxidant capacity of PZ 51 (ebselen). Biochem Pharmacol33:3235-3239,1984 115. Wendel A, Fausel M, Safayhi H, Tiegs G, Otter R: A novel biologically active seleno-organic compound. II. Activity of PZ 51 in relation to glutathione peroxidase. Biochem Pharmacol33:3241-3245,1984 116. Parnham MJ, Graf E: Seleno-organic compounds and the therapy of hydroproxide-linked pathological conditions. Biochem Pharmacol36:3095-3102,1987 117. Parnham MJ, Graf E, Khul P, et al: Seleno-organic therapy of inflammation. Adv Inflam Res 12:257-267, 1988 118. Parnham MJ, Biedermann J, Bittner CH, et al: Structure-activity relationships of a series of antiinflammatory benzisoselenazolones (BISAS). Agents Actions 27:306308,1989 119. Lipsky PE, Ziff M: Inhibition of human helper T ceil function in vitro by o-Penicillamine and CuSO4. J Clin Invest 65:1069-1076, 1980 120. Munthe E, Guldaz G, Jellum E: Increased intracellular glutathione during penicillamine treatment for rheumatoid arthritis. Lancet 2:1126-1127,1979 121. Chaudiere J, Tappel AL: Interaction of gold (I) with the active site of selenium-glutathione peroxidase. J Immunol Biochem 20:313-325, 1984 122. Hu ML, Dillard CJ, Tappel AL: Aurothioglucon effect on sulphydryls and glutathione-metabolizing enzymes: In vivo inhibition of selenium-dependent glutathione peroxidase. Res Comm Chem Path01 Pharmacol 59:147160,1988 123. Baker MA, Dillard CJ, Tappel AL: Effect of gold on selenium and glutathione peroxidase activities in rat tissues. Drug Nutr Int 3:141-152,1985 124. Cousins RJ: Absorption, transport and hepatic metabolism of copper and zinc: Special reference to metallothionein and ceruloplasmin. Physiol Rev 65:238-309, 1985 125. Peretz A, Neve J, Famaey JP: Effects of chronic and acute corticosteroid therapy on zinc and copper status in rheumatoid arthritis patients. J Trace Elem Electrol Health Dis 3:103-108, 1989