Geoffrey J. Beckett

Selenium in the Immune System

Selenium as an essential component of selenocysteine-containing protein is involved in most aspects of cell biochemistry and function. As such, there is much potential for selenium to influence the immune system. For example, the antioxidant glutathione peroxidases are likely to protect neutrophils from oxygen-derived radicals that are produced to kill ingested foreign organisms. When the functions of all selenoproteins are described, only then will it be possible to fully understand their role in maintaining optimal immune function.

Selenium: an essential element for immune function

Abstract The importance of selenium for optimal immune function is now apparent. Here, Roddie McKenzie and colleagues describe how selenium is involved in the function of immune cells, and the various immune deficiencies and diseases that result from inadequate dietary intake.

Glutathione S-transferases: biomedical applications.

Publisher Summary This chapter focuses on the biomedical applications of ubiquitous and modest size enzymes, glutathione S-transferases (GST), found in bacteria, yeast, nematodes, insects, fish, birds, and mammals. They constitute a complex supergene family that collectively metabolizes chemotherapeutic drugs, carcinogens, environmental pollutants, and a broad spectrum of other harmful foreign compounds (xenobiotics). The fact that GST is present at high levels in the liver ensures that their concentration in plasma provides an exceptionally sensitive index of hepatocellular damage. Whereas the function of GST is considered primarily to be one of detoxifying foreign compounds, these enzymes possess activities other than catalyzing the formation of glutathione–xenobiotic conjugates. For example, GST exhibit peroxidase activity toward organic hydroperoxides and serve to combat oxidative stress. The conjugation between reduced glutathione (GSH) and xenobiotics represents the few subsequent steps that lead to the formation of mercapturic acids: the removal of the γ-glutamyl moiety from the glutathione conjugate by γ-glutamyltransferase, the enzymatic removal of glycine from the cysteinyl glycine conjugate, and the N-acetylation of the cysteine conjugate by an acetyl-CoA-linked acetylase. The final N-acetylcysteine thioethers, or mercapturic acids, produced by the enzymes that catalyze this pathway are water soluble and are readily excreted from the body.

Mechanisms behind the non-thyroidal illness syndrome: an update.

The mechanisms behind the changes in serum triiodothyronine (T(3)), thyroxine (T(4)) and TSH that occur in the non-thyroidal illness syndrome (NTIS) are becoming clearer. Induction of a central hypothyroidism occurs due to a diminution in hypothalamic thyrotropin-releasing hormone. This can be signalled by a decrease in leptin caused by malnutrition and possibly a localised increase in hypothalamic T(3) catalyzed by altered expression of hypothalamic iodothyronine deiodinases D2 and D3. Data from D1 and D2 knockout mice suggest that these enzymes may have little contribution to the low serum T(3) found in acute illness. The decline in serum T(3) and T(4) in models of acute illness precedes the fall in hepatic D1, suggesting that much of the initial fall in these hormones may be attributable to an acute phase response giving rise to a reduction in the thyroid hormone binding capacity of plasma. When measured by reliable methods, changes in serum free T(4) and free T(3) are modest in comparison to the fall seen in total thyroid hormone. Thyroid hormone transporter expression is up-regulated in many models of the NTIS, thus if diminished tissue uptake of hormone occurs in vivo, it is likely to be the result of impaired transporter function caused by diminished intracellular ATP or plasma inhibitors of transporter action. In man, chronic illness leads to an upregulation of thyroid hormone receptor (THR) expression at least in liver and renal failure. In contrast, human and animal models of sepsis and trauma indicate that expression of THRs and their coactivators are decreased in acute illness.

Genetic polymorphisms in the human selenoprotein P gene determine the response of selenoprotein markers to selenium supplementation in a gender-specific manner (the SELGEN study)

Selenium (Se), a micronutrient essential for human health, is incorporated into at least 25 selenoproteins including selenoprotein P (SePP)′ which transports Se within the body. This research identified two single nucleotide polymorphisms (SNPs) in the SePP gene, one in the coding region (position 24731, causing an Ala to Thr change) and one in the 3′untranslated region (position 25191). Their frequency was similar in Caucasian, Chinese, and South Asian populations. Prospectively geno‐typed volunteers were supplemented for 6 wk with 100 μg sodium selenite/day. Blood samples were analyzed for plasma Se and selenoprotein biomark‐ers at baseline, after supplementation, and during a washout period. Plasma Se, SePP, and glutathione peroxidase 3 (GPx3) levels increased with supplementation. Baseline plasma Se content depended on both SePP genotypes and body mass index. Pre‐supplementation SePP concentration was associated with gender and genotype at SNP 24731 and post‐supplementation concentration with SNP 25191. Both SNPs and gender were associated with differences in GPx3 activity, plasma, and erythrocyte thioredoxin reductase 1 concentrations and lymphocyte glutathione peroxidase 1 and 4 activities and concentrations. In conclusion, the data reveal two common functional SNPs within the human SePP gene that may predict behavior of biomarkers of Se status and response to supplementation and thus susceptibility to disease.—Méplan, C., Crosley, L. K., Nicol, F., Beckett, G. J., Howie, A. F., Hill, K. E., Horgan, G., Mathers, J. C., Arthur, J. R., Hesketh, J. E. Genetic polymorphisms in the human selenoprotein P gene determine the response of selenoprotein markers to selenium supplementation in a gender‐specific manner (the SELGEN study) FASEB J. 21, 3063–3074 (2007)

A NEW STRATEGY FOR THYROID FUNCTION TESTING

In view of the increasing number of in-vitro tests of thyroid function, rationalization of the biochemical assessment of patients with suspected thyroid disease was attempted. In addition to clinical examination of 285 consecutive new referrals to a thyroid clinic, measurements were made of serum total and free triiodothyronine (T3) and thyroxine (T4) and of thyrotropin (TSH) by radioimmunoassay before and 20 min after thyrotropin-releasing hormone (TRH) and basal TSH by immunoradiometric assay (IRMA). Analysis of these results demonstrated that: (i) a detectable and normal TSH (IRMA) result indicates that the patient is euthyroid and obviates the need for measurement of thyroid hormones and (ii) a raised or undetectable TSH (IRMA) level should be followed by measurement of free T4 (and rarely also free T3) to distinguish between subclinical and overt hypothyroidism and hyperthyroidism. This policy would considerably reduce the number of in-vitro thyroid function tests without resulting in either a delay in diagnosis or a reduction in its accuracy.

A sensitive immunoradiometric assay for serum thyroid stimulating hormone: a replacement for the thyrotrophin releasing hormone test?

The value as a thyroid function test of a new, rapid, and highly sensitive immunoradiometric assay for thyroid stimulating hormone (TSH) was assessed in 188 consecutive new patients with suspected hyperthyroidism. The diagnosis was made on clinical grounds and on the basis of serum total triiodothyronine and thyroxine concentrations and the response of TSH to thyrotrophin releasing hormone (TRH) as measured by radioimmunoassay. In all except one patient the basal TSH concentration by immunoradiometric assay predicted the response of TSH by radioimmunoassay to TRH, an undetectable value being recorded in patients with a subnormal response and a measurable value in those with a normal test result. This clear relation was not observed for basal TSH concentrations as measured by radioimmunoassay. In a series of 39 hospital inpatients with acute or chronic non-thyroidal illness, of whom 11 had low concentrations of total thyroxine or triiodothyronine, or both, basal TSH concentrations were detectable by both radioimmunoassay and immunoradiometric assay in all cases and were associated with normal responses to TRH. The immunoradiometric assay for TSH, which is commercially available, may therefore obviate the need for the more time consuming TRH test and simplify the approach to thyroid function testing in patients with suspected hyperthyroidism.

Selenium and the regulation of cell signaling, growth, and survival: molecular and mechanistic aspects.

In the past 30 years, it has been recognized that dietary selenium (Se) is essential for the normal function of many of the systems of the body. Furthermore, low Se intake can have deleterious effects on several aspects of human and animal health. The importance of Se is characterized in its role as a constituent of several key antioxidant and redox enzyme families. Most of the effects of Se are probably mediated by selenoproteins, which have the micronutrient covalently incorporated into the protein. The purpose of this review is to examine basic mechanisms by which Se regulates cell growth, gene transcription, cell signaling, and cell death. We start with the historical background to Se. The synthesis and function of selenoproteins are described, followed by details of the dietary sources of Se and Se status in different parts of the world, together with the clinical effects of Se deficiency and toxicity. We consider some aspects of the molecular mechanisms by which Se modulates cell growth, intracellular signaling, and gene transcription.

The developmental expression of alpha-, mu- and pi-class glutathione S-transferases in human liver

The developmental expression of the alpha, mu and pi class glutathione S-transferases has been defined in human liver using radioimmunoassay and immunohistochemistry. Expression of alpha and mu class isoenzymes increased significantly at birth, while that of the pi isoenzyme declined during the first trimester. Mu-class isoenzymes (GST1 1, GST1 2, GST1 2-1) were expressed in hepatocytes but not in other liver cell types.

The role of selenium in thyroid hormone metabolism and effects of selenium deficiency on thyroid hormone and iodine metabolism

Selenium deficiency impairs thyroid hormone metabolism by inhibiting the synthesis and activity of the iodothyronine deiodinases, which convert thyroxine (T4) to the more metabolically active 3,3′–5 triiodothyronine (T3). Hepatic type I iodothyronine deiodinase, identified in partially purified cell fractions using affinity labeling with [125I]N-bromoacetyl reverse triiodothyronine, is also labeled with75Se by in vivo treatment of rats with75Se−Na2SeO3. Thus, the type I iodothyronine 5′-deiodinase is a selenoenzyme. In rats, concurrent selenium and iodine deficiency produces greater increases in thyroid weight and plasma thyrotrophin than iodine deficiency alone. These results indicate that a concurrent selenium deficiency could be a major determinant of the severity of iodine deficiency.