Selenium

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References

Berkson BM. A conservative triple antioxidant approach to the treatment of hepatitis C. Combination of alpha lipoic acid (thioctic acid), silymarin, and selenium: three case histories. Med Klin. 1999 Oct 15;94 Suppl 3:84-89.
Abstract: BACKGROUND: There has been an increase in the number of adults seeking liver transplantation for hepatitis C in the last few years and the count is going up rapidly. There is no reliable and effective therapy for chronic hepatitis C since interferon and antivirals work no more than 30% of the time, and liver transplant surgery is uncertain and tentative over the long run. This is because, ultimately, residual hepatitis C viremia infects the new liver. Furthermore, liver transplantation can be painful, disabling and extremely costly. TREATMENT PROGRAM: The author describes a low cost and efficacious treatment program in 3 patients with cirrhosis, portal hypertension and esophageal varices secondary to chronic hepatitis C infection. This effective and conservative regimen combines 3 potent antioxidants (alpha-lipoic acid [thioctic acid], silymarin, and selenium) that possess antiviral, free radical quenching and immune boosting qualities. CONCLUSION: There are no remarkably effective treatments for chronic hepatitis C in general use. Interferon and antivirals have less than a 30% response rate and because of the residual viremia, a newly transplanted liver usually becomes infected again. The triple antioxidant combinaton of alpha-lipoic acid, silymarin and selenium was chosen for a conservative treatment of hepatitis C because these substances protect the liver from free radical damage, increase the levels of other fundamental antioxidants, and interfere with viral proliferation. The 3 patients presented in this paper followed the triple antioxidant program and recovered quickly and their laboratory values remarkably improved. Furthermore, liver transplantation was avoided and the patients are back at work, carrying out their normal activities, and feeling healthy. The author offers a more conservative approach to the treatment of hepatitis C, that is exceedingly less expensive. One year of the triple antioxidant therapy described in this paper costs less than $2,000, as compared to more than $300,000 a year for liver transplant surgery. It appears reasonable, that prior to liver transplant surgery evaluation, or during the transplant evaluation process, the conservative triple antioxidant treatment approach should be considered. If these is a significant betterment in the patient's condition, liver transplant surgery may be avoided.


Buist RA. Drug-nutrient interactions - an overview. Intl Clin Nutr Rev 1984;4(3):114. (Review)

Clark LC, Dalkin B, Krongrad A, Combs GF Jr, Turnbull BW, Slate EH, Witherington R, Herlong JH, Janosko E, Carpenter D, Borosso C, Falk S, Rounder J. Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br J Urol. 1998 May;81(5):730-734.
Abstract: OBJECTIVE: To test if supplemental dietary selenium is associated with changes in the incidence of prostate cancer. PATIENTS AND METHOD: A total of 974 men with a history of either a basal cell or squamous cell carcinoma were randomized to either a daily supplement of 200 microg of selenium or a placebo. Patients were treated for a mean of 4.5 years and followed for a mean of 6.5 years. RESULTS: Selenium treatment was associated with a significant (63%) reduction in the secondary endpoint of prostate cancer incidence during 1983-93. There were 13 prostate cancer cases in the selenium-treated group and 35 cases in the placebo group (relative risk, RR=0.37, P=0.002). Restricting the analysis to the 843 patients with initially normal levels of prostate-specific antigen (< or = 4 ng/mL), only four cases were diagnosed in the selenium-treated group and 16 cases were diagnosed in the placebo group after a 2 year treatment lag, (RR=0.26 P=0.009). There were significant health benefits also for the other secondary endpoints of total cancer mortality, and the incidence of total, lung and colorectal cancer. There was no significant change in incidence for the primary endpoints of basal and squamous cell carcinoma of the skin. In light of these results, the 'blinded' phase of this trial was stopped early. CONCLUSIONS: Although selenium shows no protective effects against the primary endpoint of squamous and basal cell carcinomas of the skin, the selenium-treated group had substantial reductions in the incidence of prostate cancer, and total cancer incidence and mortality that demand further evaluation in well-controlled prevention trials.

Clark LC, Combs GF Jr, Turnbull BW, Slate EH, Chalker DK, Chow J, Davis LS, Glover RA, Graham GF, Gross EG, Krongrad A, Lesher JL Jr, Park HK, Sanders BB Jr, Smith CL, Taylor JR. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA. 1996 Dec 25;276(24):1957-1963.
Abstract: OBJECTIVE: To determine whether a nutritional supplement of selenium will decrease the incidence of cancer. DESIGN: A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial. SETTING: Seven dermatology clinics in the eastern United States. PATIENTS: A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years. INTERVENTIONS: Oral administration of 200 microg of selenium per day or placebo. MAIN OUTCOME MEASURES: The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers. RESULTS: After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR; 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred. CONCLUSIONS: Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made.

Combs GF Jr, Clark LC, Turnbull BW. Reduction of cancer mortality and incidence by selenium supplementation. Med Klin. 1997 Sep 15;92 Suppl 3:42-45.
Abstract: PATIENTS AND METHOD: In order to test the hypothesis that a dietary supplement of selenium (Se) may reduce cancer risk, 1312 patients with histories of basa/squamous cell carcinomas of the skin were assigned in random, double-blind fashion to daily oral supplements of either Se-enriched yeast (200 micrograms Se/day), or a low-Se yeast placebo. Patients were recruited in 1983 to 1990 and were followed with regular dermatologic examinations through, 1993 for a total of 8269 person-years of observation. Skin cancer diagnoses were confirmed histologically and plasma Se concentration was determined at 6 to 12 months intervals. All deaths and patient-reported illnesses were confirmed and documented by consultation with the patient medical care providers. RESULTS: Results showed that Se-supplementation did not significantly affect the incidences of recurrent basal/squamous cell carcinomas of the skin. However, Se-treatment was associated with reductions in total cancer mortality and in the incidences of lung, colorectal, prostate and total cancers. These effects were consistent over time and between study clinics. CONCLUSION: The results strongly suggest benefits of Se-supplementation for this cohort of patients and support the hypothesis that supplemental Se can reduce risks to at least some types of cancer.

Combs GF Jr, Clark LC, Turnbull BW. Reduction of cancer risk with an oral supplement of selenium. Biomed Environ Sci. 1997 Sep;10(2-3):227-234.
Abstract: The hypothesis that a dietary supplement of selenium (Se) may reduce cancer risk was tested experimentally in humans. Patients with histories of basal/squamous cell carcinomas of the skin were assigned randomly in double-blind fashion to daily oral supplements of either Se-enriched yeast (200 micrograms Se/day), or a low-Se yeast placebo. A total of 1312 patients recruited in 1983-1990 were followed with regular dermatologic examinations through 1993 for a total of 8269 person-years of observation. Skin cancer diagnoses were confirmed histologically. Plasma Se concentration was determined at 6-12 months intervals. All deaths and patient-reported illnesses were recorded; reported cancers were confirmed and documented by consultation with the patient medical care providers. The results indicate that Se did not significantly affect the primary endpoints: incidences of recurrent basal/squamous cell carcinomas of the skin. However, Se-treatment was associated with reductions in several secondary endpoints: total mortality, mortality from all cancers combined, as well as the incidence of all cancers combined, lung cancer, colorectal cancer and prostate cancer. The consistencies of these associations over time, between study clinics and for the leading cancer sites strongly suggests benefits of Se-supplementation for this cohort of patients, supporting the hypothesis that supplemental Se can reduce cancer risk. Although Se did not shown protective effects against non-melanoma skin cancers, the suggested reductions in risks to other frequent cancers demand further evaluation in well controlled clinical intervention trials.

Contempre B, Dumont JE, Ngo B, Thilly CH, Diplock AT, Vanderpas J. Effects of selenium supplementation in hypothyroid subjects of an iodine and selenium deficient area: The possible danger of indiscriminate supplementation of iodine deficient subjects with selenium. J Clin Endocrinol Metabol 1991 Jul;73(1):213-215.
Abstract: Selenium and seleno dependent glutathione peroxidase (GPX) deficiency has been described in endemias of myxedematous cretinism. In northern Zaire, a selenium supplementation trial has been conducted. Beside correcting the GPX activity, two months of selenium supplementation was shown to modify the serum thyroid hormones parameters in clinically euthyroid subjects and to induce a dramatic fall of the already impaired thyroid function in clinically hypothyroid subjects. These results further support a role of selenium in thyroid hormone metabolism. In an iodine deficient area, this selenium deficiency could lead to opposite clinical consequences: protect the general population and the fetus against iodine deficiency and brain damage; and in turn, favour the degenerative process of the thyroid gland leading to myxoedematous cretinism.

Dorgan JF, Sowell A, Swanson CA, Potischman N, Miller R, Schussler N, Stephenson HE Jr. Relationships of serum carotenoids, retinol, alpha-tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri. Cancer Causes Control. 1998 Jan;9(1):89-97.
Abstract: To evaluate relationships of serum carotenoids, alpha-tocopherol, selenium, and retinol with breast cancer prospectively, we conducted a case-control study nested in a cohort from the Breast Cancer Serum Bank in Columbia, Missouri (United States). Women free of cancer donated blood to this bank in 1977-87. During up to 9.5 years of follow-up (median = 2.7 years), 105 cases of histologically confirmed breast cancer were diagnosed. For each case, two women alive and free of cancer at the age of the case's diagnosis and matched on age and date of blood collection were selected as controls. A nonsignificant gradient of decreasing risk of breast cancer with increasing serum beta-cryptoxanthin was apparent for all women. Serum lycopene also was associated inversely with risk, and among women who donated blood at least two years before diagnosis, a significant gradient of decreasing breast cancer risk with increasing lycopene concentration was evident. A marginally significant gradient of decreasing risk with increasing serum lutein/zeaxanthin also was apparent among these women. We did not observe any evidence for protective effects of alpha- and beta-carotene, alpha-tocopherol, retinol, or selenium for breast cancer. Results of this study suggest that the carotenoids beta-cryptoxanthin, lycopene, and lutein/zeaxanthin may protect against breast cancer.

Dworkin BM. Selenium deficiency in HIV infection and the acquired immunodeficiency syndrome (AIDS). Chem Biol Interact. 1994 Jun;91(2-3):181-186. (Review)
Abstract: Selenium is required for activity of the enzyme glutathione peroxidase, and selenium deficiency may be associated with myopathy, cardiomyopathy and immune dysfunction including oral candidiasis, impaired phagocytic function and decreased CD4 T-cells. We assessed selenium status in 12 patients with AIDS compared to normals and found significantly low plasma and red blood cell levels. Plasma selenium in AIDS was 0.043 +/- 0.01 microgram/ml vs 0.095 +/- 0.016 in controls (P < 0.001). Selenium status correlated with serum albumin (r = 0.77; P < 0.001) and 60% had documented GI malabsorption as determined by abnormal D-Xylose tests. In a subsequent study blood selenium and glutathione peroxidase were diminished in 12 AIDS and 8 ARC patients compared with normals (all P < 0.001). For glutathione peroxidase the mean levels were decreased by 45% in AIDS and 27% in ARC versus controls (P < 0.001). Both plasma selenium and glutathione peroxidase significantly correlated with total lymphocyte counts (r = 0.65; P < 0.001; glutathione peroxidase and lymphocyte counts). This occurred in both homosexuals and drug users with AIDS and irrespective of the presence or absence of diarrhea or GI malabsorption. To determine if tissue levels of selenium were also depleted we studied cardiac selenium levels in autopsy AIDS hearts compared to age and sex matched controls. Cardiac selenium in AIDS was 0.327 +/- 0.082 micrograms/g dry weight versus 0.534 +/- 0.184 in controls (P < 0.01). Two cases had histologic cardiomyopathy pathologically consistent with the cardiomyopathy described in Keshan disease associated with low selenium blood levels. To further assess mechanisms of nutrient and selenium deficiency in AIDS we studied dietary intake in outpatients and inpatients with various stages of HIV infection. Inadequate selenium intake based on a computer (Nutritionist 3) analysis of 72 h diet records was present in only 17% of clinically stable HIV positive outpatients and 71% of inpatients with AIDS. Conclusions: Selenium deficiency is common in HIV positive patients as documented by low plasma and red blood cell levels of selenium, diminished activity of glutathione peroxidase, and low cardiac selenium levels in AIDS hearts. Patients with AIDS tend to have more severe deficits than those with earlier stages of HIV infection. The selenium deficit in blood does correlate with serum albumin levels and total lymphocyte counts. Poor dietary intake and malabsorption could lead to this condition which has important implications for both cardiac and immune functions in HIV positive patients.

Graf WD, Oleinik OE, Glauser TA, Maertens P, Eder DN, Pippenger CE. Altered antioxidant enzyme activities in children with a serious adverse experience related to valproic acid therapy. Neuropediatrics 1998 Aug;29(4):195-201.
Abstract: Specific oxidative metabolites of valproic acid (VPA) have been associated with the clinically defined toxicity of the drug. To investigate the role of enzymatic detoxification in clinical toxicity, we compared activities of five antioxidant enzymes in 15 patients with a serious adverse experience (SAE) related to VPA therapy, to enzyme activities measured in 35 patients with good clinical tolerance of VPA, and 50 healthy, age-matched subjects. These enzymes included glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), glutathione transferase, superoxide dismutase, and catalase in erythrocytes; and GSH-Px in plasma. We also determined levels of Se, Cu, and Zn, trace elemental cofactors for these enzymes, in plasma from each individual. In patients with a VPA-associated SAE, GSH-Px was significantly depressed and GSSG-R was significantly elevated relative to values for the other groups. Selenium and zinc concentrations were lower in SAE patients than in controls. These findings may indicate a role for selenium dependent antioxidant activity in individual susceptibility to an SAE related to VPA therapy.

Heese HD, Lawrence MA, Dempster WS, Pocock F. Reference concentrations of serum selenium and manganese in healthy nulliparas. S Afr Med J 1988 Feb 6;73(3):163-165.
Abstract: Reference serum selenium and manganese concentrations were established for healthy nulliparas aged 18-23 years resident in Cape Town. Measurements were determined for selenium in 100 female students who had been taking low-dosage triphasic contraceptive medication for a minimum of 3 months and in 100 female students who were not on contraceptive therapy. Manganese concentrations were determined for 25 female students from each group. The mean serum selenium concentrations were 0.988 +/- 0.189 micrograms/l (78 +/- 15 micrograms/dl) and 0.925 +/- 0.177 mumol/l (73 +/- 14 micrograms/l) respectively for females taking and not taking oral contraceptives. The corresponding concentrations for manganese were 21.84 +/- 9.82 nmol/l (1.20 +/- 0.54 micrograms/l) and 21.66 +/- 7.64 nmol/l (1.19 +/- 0.42 micrograms/l) respectively. The differences in selenium were statistically significant (P = 0.0231) but not for manganese (P = 0.910).

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998.

Hou JC, Jiang ZY, He ZF. [Inhibitory effect of selenium on complement activation and its clinical significance]. Chung Hua I Hsueh Tsa Chih. 1993 Nov;73(11):645-6, 699. [Article in Chinese]
Abstract: In immunopathological study of complement activation, we recognised a marked inhibitory effect of sodium selenite on the haemolysis induced by complement fixation in vitro, thereafter on mouse complement activation in vivo induced by endotoxin, inulin or aggregated IgG indicated by a special rocket immunoelectrophoresis test of C3 split products. The effective inhibition usually began at the concentration of 0.002 mol/L of selenite in vitro, and 20 micrograms/25 g BW intravenously in vivo. The inhibitory effect was found evident on alternative pathway. This inhibitory effect was further identified in cases of epidemic haemorrhagic fever (EHF) treated by multiple dosages of 2 mg selenite per day in the first 9 days of hospitalization other than general management of 80 severe cases, including fulminant and moderate grade EHF cases. C3 activation was inhibited accordingly and the mortalities also dropped markedly from 100% of the non-treated group to 36% of the selenite treated group of fulminant type, and from 22% to zero of severe type group.

Hurd RW, Van Rinsvelt HA, Wilder BJ, Karas B, Maenhaut W, De Reu L. Selenium, zinc, and copper changes with valproic acid: possible relation to drug side effects. Neurology 1984 Oct;34(10):1393-1395.
Abstract: Side effects of treatment with the anticonvulsant valproic acid (VPA) suggested the possibility of alteration of trace metal status. Administration of VPA for 1 week produced significant depletion of zinc and selenium in plasma of rats and a one-third reduction of hepatic selenium. Patients who were treated chronically, with VPA as the sole anticonvulsant medication, had decreased plasma selenium levels. Most cases of VPA-associated hepatotoxicity occur in children. This could be due to decreased selenium concentrations when mechanisms for protection against peroxidative damage are not fully developed.

Karakucuk S, Ertugrul Mirza G, Faruk Ekinciler O, Saraymen R, Karakucuk I, Ustdal M. Selenium concentrations in serum, lens and aqueous humour of patients with senile cataract. Acta Ophthalmol Scand. 1995 Aug;73(4):329-332.
Abstract: Selenium (Sc) is a trace element which incorporates into the selenoenzyme glutathion peroxidase. Cataractogenesis may be caused either by the excess or deficiency of this trace element. More recently, its potential of becoming a possible environmental pollutant has been emphasized. In an attempt to reveal the relationship of this element with cataractogenesis, we detected its level in 48 serum, 36 lens and 9 aqueous humour samples of 48 patients with senile cataract, comparing the results with appropriate controls. Selenium levels (mean +/- SD) of cataractous patients were found to be 0.28 +/- 0.04 microgram/ml (CI: 0.27 to 0.29 microgram/ml) in sera (controls: 0.32 +/- 0.04 microgram/ml; CI: 0.30 to 0.34 microgram/ml, p < 0.0001), 5.43 +/- 3.07 microgram/g dry weight (CI: 4.43 to 6.43 microgram/g dry weight) in lens (controls: 4.43 +/-2.53 microgram/g dry weight; CI: 2.78 to 6.08 microgram/g dry weight; p=0.374) and 0.19 +/- 0.06 microgram/ml (CI:0.15 to 0.23 microgram/ml) in aqueous humour samples (controls: 0.31 +/-0.12 microgram/ml; CI: 0.24 to 0.38 microgram/ml, p = 0.02). When patient subgroups were analyzed, serum Se levels were found to be 0.28 +/- 0.05 microgram/ml (CI: 0.26 to 0.30 microgram/ml in the nuclear cataract and 0.28 +/- 0.02 microgram/ml (CI: 0.27 to 0.30 microgram/ml) in the cortical cataract. Lens Se levels, on the other hand, were detected as 5.91 +/- 3.56 microgram/g dry weight (CI:4.49 to 7.33 microgram/g dry weight) in the nuclear cataract and 4.47 +/- 1.40 microgram/g dry weight (CI: 3.68 to 5.26 microgram/g dry weight) in the cortical cataract. It is anticipated that decreased Se in aqueous humour and sera of patients with senile cataract may reflect defective antioxidative defense systems which may lead to the formation of cataract.

Longnecker MP, Stram DO, Taylor PR, Levander OA, Howe M, Veillon C, McAdam PA, Patterson KY, Holden JM, Morris JS, Swanson CA, Willett WC. Use of selenium concentration in whole blood, serum, toenails, or urine as a surrogate measure of selenium intake. Epidemiology. 1996 Jul;7(4):384-390.
Abstract: We examined the validity of using the selenium level in a single biological specimen as a surrogate measure of usual intake. We used data from 77 free-living adults from South Dakota and Wyoming. Subjects provided multiple 1-day duplicate-plate food composites, repeated specimens of blood and toenails, and 24-hour urine collections. We developed a statistical calibration method that incorporated measurement error correction to analyze the data. The Pearson correlation coefficients between selenium intake and a single selenium status measure, after deattenuation to adjust for the effect of within-person variation in intake, were: 0.78 for whole blood, 0.74 for serum, 0.67 for toenails, and 0.86 for urine. We present formulas to estimate the intake of individuals, based on selenium levels in a single specimen of blood, toenails, or urine. In these data, the concentration of selenium in a single specimen of whole blood, serum, or toenails served reasonably well as a measure for ranking subjects according to long-term selenium intake but provided only a rough estimate of intake for each subject.

Luoma P. Antioxidants, infections and environmental factors in health and disease in northern Finland. Int J Circumpolar Health 1998 Jul;57(2-3):109-113.
Abstract: Recent studies have identified several factors which may affect human health and life expectancy in northern Finland. They have shown that antioxidants, infections, genetic or environmental factors may affect the development of and morbidity/mortality from cardiovascular diseases, cancer, diabetes mellitus and other diseases in the northern provinces of this country. Both the occurrence and mortality from coronary heart disease (CHD) is low in the northernmost part of the country, i.e. Mountain Lapland or the Saami area, compared with that in whole country or a neighbouring region to the south in central Lapland. The mortality from all diseases is also low in communities in Mountain Lapland, and high in central Lapland in communities such as Kittila and Kolari. High scrum antioxidants, alpha-tocopherol (vitamin E), albumin and selenium levels have been measured in men living in the northernmost part of the country, where the death rate from CHD is low. Low serum alpha-tocopherol and albumin levels were typical of men living in rural communities with high CHD mortality, e.g. Kittila community. Serum antioxidant levels were related to the diet; alpha-tocopherol increased with the consumption of reindeer meat and selenium with fish consumption. Our earlier studies have also identified a low Chlamydia pneumoniae IgA antibody titer in men living in Mountain Lapland compared with men in the neighboring region to the south in central Lapland with high CHD mortality. An elevated Chlamydia pneumoniae IgA antibody titer was associated with low serum alpha-tocopherol level. The people of Saami origin, an ethnic minority living in northernmost Finland, have a high apolipoprotein (apo) E e4 allele frequency and high serum cholesterol. They also have more apo A-IV-2 allele than most of the studied populations, and their HDL cholesterol levels are higher in apo A-IV-2/1 than in apo A-IV-1/1 phenotypes. Our earlier studies indicate that people living in northeastern Finland, west of smelters in Kola Peninsula may be exposed to heavy metals such as cadmium and mercury. Blood cadmium was related to blood pressure and high in men with arterial hypertensive disease. The investigations presented in this article form a good basis for further studies that clarify underlying reasons the health problems in the north.

Moore JA, Noiva R, Wells IC. Selenium concentrations in plasma of patients with arteriographically defined coronary atherosclerosis. Clin Chem 1984;30:1171-1173.

Nurge ME, Anderson CR, Bates E. Metabolic and nutritional implications of valproic acid. Nutr Res 1991;11:949-960.

Olas B, Wachowicz B. [Selenium in the cytotoxicity of cisplatin]. Postepy Hig Med Dosw 1997;51(1):95-108. [Article in Polish]
Abstract: Cisplatin is a widely used chemotherapeutic agent, highly effective in the treatment of various types of human malignancies. The antitumor activity of cisplatin is attributed mainly to its ability to form adducts with DNA. Cisplatin may react with proteins and also with glutathione forming complex GS-Pt. This agent causes haematological, neurological toxicity and changes function of different cells. Recently, is has been reported that administration of sodium selenite reduces cisplatin toxicity without inhibiting the antitumour activity of cisplatin. This review focuses on the mechanism of cisplatin-induced cytotoxicity and the protective role of selenium.

Peretz A, Neve J, Duchateau J, Siderova V, Huygen K, Famaey JP, Carpentier YA. Effects of selenium supplementation on immune parameters in gut failure patients on home parenteral nutrition. Nutrition. 1991 May-Jun;7(3):215-221.

Peretz A, Neve J, Desmedt J, Duchateau J, Dramaix M, Famaey JP. Lymphocyte response is enhanced by supplementation of elderly subjects with selenium-enriched yeast. Am J Clin Nutri 1991;May;53(5):1323-1328.
Abstract: The effect of selenium supplementation on plasma selenium concentrations and lymphocyte-proliferation responses to mitogens was investigated in 22 elderly institutionalized subjects. Subjects were assigned to a 6-mo trial with either 100 micrograms Se/d (as selenium-enriched yeast) or a placebo. Plasma selenium concentrations of the selenium-supplemented group increased from 0.84 +/- 0.26 to 1.55 +/- 0.33 mumol/L (mean +/- SD) after 2 mo and the values plateaued thereafter. The mean response of lymphocytes to mitogens in elderly subjects tended to be lower than responses in healthy adults, although responses remained within the 5-95% confidence-interval limit for healthy adults. During selenium supplementation the proliferative response to pokeweed mitogen increased significantly (+79% of baseline concentrations after 4 mo, P less than 0.01) and reached the upper limit of the usual range for adults after 6 mo (+138%, P less than 0.001). In accordance with previous studies in animals and in vitro, this investigation demonstrates for the first time immunostimulatory properties of selenium-enriched yeast in elderly humans.

Peretz A, Neve J, Famaey J. Selenium in rheumatic diseases. Semin Arthritis Rheum. 1991 Apr;20(5):305-316. (Review)
Abstract: 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 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.

Peretz A, Neve J, Vertongen F, Famaey JP, Molle L. Selenium status in relation to clinical variables and corticosteroid treatment in rheumatoid arthritis. J Rheumatol. 1987 Dec;14(6):1104-1107.
Abstract: Plasma selenium levels, erythrocyte selenium levels and activity of the selenoenzyme glutathione peroxidase in erythrocytes were determined in patients with rheumatoid arthritis (RA) and acute inflammatory arthritis. Results were compared with those from age and sex matched controls. These variables were not statistically different from controls in patients with inflammatory arthritis and in patients with RA not treated with corticosteroids. No correlation was found in RA between plasma selenium biological variables of inflammation and most clinical indices of disease severity. Therefore, acute or chronic inflammation was not the main factor that accounted for low plasma selenium levels in RA. Corticosteroid treatment, particularly at high doses (20-60 mg prednisolone/day), was significantly related to the depressed plasma selenium levels of some patients with RA. The mechanisms underlying this modification remain poorly understood.

Pronsky Z. Powers and Moore's Food-Medications Interactions. Ninth Edition. Food-Medication Interactions. Pottstown, PA, 1991, 60.

Robinson C, Weigly E. Basic Nutrition and Diet Therapy. New York: MacMillan, 1984.

Roe DA. Diet and Drug Interactions. New York: Van Nostrand Reinhold, 1989.

Roe DA. Drug-induced Nutritional Deficiencies. 2nd ed. Westport, CT: Avi Publishing, 1985.

Roe DA. Risk factors in drug-induced nutritional deficiencies. In: Roe DA, Campbell T, eds. Drugs and Nutrients: The Interactive Effects. New York: Marcel Decker, 1984: 505-523.

Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: biochemical role as a component of glutathione peroxidase. Science. 1973 Feb 9;179(73):588-590.

Scott R, MacPherson A, Yates RW, Hussain B, Dixon J. The effect of oral selenium supplementation on human sperm motility. Br J Urol. 1998 Jul;82(1):76-80.
Abstract: OBJECTIVES: To determine whether the decline in selenium intake and selenium status in men in the West of Scotland might be a contributory factor to male subfertility. PATIENTS AND METHODS: Two semen samples were collected from patients attending a subfertility clinic and those patients with samples showing reduced motility were invited to participate in an ethically approved double-blind clinically controlled trial with informed consent. Sixty-nine patients were recruited and received either placebo, selenium alone or selenium plus vitamins A, C and E daily for 3 months. A further semen sample was collected at the end of the trial. Plasma selenium status was determined at the beginning and end of the trial period, as was total sperm density and motility. RESULTS: Plasma selenium concentrations were significantly (P < 0.001) higher in both selenium-treated groups than in controls. No significant effect of treatment on sperm density was recorded. Sperm motility increased in both selenium-treated groups, in contrast to a slight decline in the placebo group, but the difference was not significant. However, as the provision of additional vitamins had no effect on any variable measured it was considered justified to combine the two selenium-treated groups and compare them with the placebo treatment. On this basis, selenium treatment significantly (P < 0.002) increased plasma selenium concentrations and sperm motility (P = 0.023) but sperm density was again unaffected. Five men (11%) achieved paternity in the treatment group, in contrast to none in the placebo group. CONCLUSION: This trial confirms the result of an earlier study, that selenium supplementation in subfertile men with low selenium status can improve sperm motility and the chance of successful conception. However, not all patients responded; 56% showed a positive response to treatment. The low selenium status of patients not supplemented again highlights the inadequate provision of this essential element in the Scottish diet.

Swanson AA, Truesdale AW. Elemental analysis in normal and cataractous human lens tissue. Biochem Biophys Res Commun. 1971 Dec 17;45(6):1488-1496.

Swanson CA, Patterson BH, Levander OA, Veillon C, Taylor PR, Helzlsouer K, McAdam PA, Zech LA.Human [74Se]selenomethionine metabolism: a kinetic model. Am J Clin Nutr 1991 Nov;54(5):917-926.
Abstract: A study was undertaken to investigate the pharmacokinetics of an organically bound form of selenium. Six adults received a single oral 200-micrograms dose of 74Se as L-selenomethionine. A kinetic model was developed to simultaneously account for the appearance and disappearance of the tracer in plasma, urine, and feces. The model included absorption distributed along the gastrointestinal tract, uptake by the liver-pancreas subsystem, enterohepatic recirculation, distribution to two large tissue pools, and transport through four components of the plasma pool. Average turnover time of the plasma components varied from 0.01 to 1.1 d. The turnover time in the liver-pancreas subsystem ranged from 1.6 to 3.1 d. Turnover time ranged from 61 to 86 d in the peripheral tissues with the slowest turnover. The whole-body residence time was approximately five-fold greater than the turnover time of the tissue pool with the slowest turnover, reflecting substantial reutilization of labeled material.

Tabatabaei AR, Abbott FS. Assessing the mechanism of metabolism-dependent valproic acid-induced in vitro cytotoxicity. Chem Res Toxicol 1999 Apr;12(4):323-330.
Abstract: This study was designed to distinguish and evaluate the contribution of reactive metabolite and reactive oxygen species as the mechanism of metabolism-dependent valproic acid-induced in vitro cytotoxicity. The involvement of reactive oxygen species in the mechanism of in vitro cytotoxicity was examined by the addition of a series of antioxidant enzymes and iron chelators to the reaction mixture. Addition of catalase to the reaction mixture resulted in a complete prevention of valproic acid-induced cytotoxicity. Co-incubation of a cell impermeable iron chelator deferoxamine did not effect cytotoxicity, whereas 1,10-phenanthroline, a chelator with the ability to traverse cell membranes at low concentrations, afforded significant protection against valproic acid-induced cytotoxicity. A possible inhibitory effect of catalase and 1,10-phenanthroline on the microsomal metabolism of valproic acid was disproved by the quantification of valproic acid metabolites in the presence and absence of these compounds. To assess the specificity of the mechanism of in vitro valproic acid-induced cytotoxicity, prevention of in vitro acetaminophen-induced cytotoxicity by antioxidant enzymes and iron chelators was also evaluated. Addition of catalase to the reaction mixture in the presence of acetaminophen resulted in a moderate reduction in the level of but a lack of complete protection of cytotoxicity. Addition of 1,10-phenanthroline to the reaction mixture in the presence of acetaminophen did not result in a detectable change in acetaminophen-induced cytotoxicity. These data suggest the involvement of reactive oxygen species in the mechanism of toxicity of valproic acid and perhaps reactive metabolites as the major cause of cytotoxicity in the case of acetaminophen in the in vitro model investigated. Inhibition of poly(ADP-ribose) polymerase activity by various antagonists resulted in complete prevention of valproic acid-induced in vitro cytotoxicity. The cytoprotective effects of known poly(ADP-ribose) polymerase antagonists implicate poly(ADP-ribose) polymerase in the mechanism of in vitro metabolism-dependent valproic acid-induced cytotoxicity under these conditions. These results further point to nuclear DNA as the intracellular site of insult by the generated oxygen radicals. Overall, the data obtained support the hypothesis that the metabolism-dependent valproic acid-induced in vitro cytotoxicity is the result of generation of hydrogen peroxide in the medium that can readily cross cell membranes and subsequently interact intracellularly with iron to produce the highly reactive hydroxyl free radicals.

Trovato A, Nuhlicek DN, Midtling JE. Drug-nutrient interactions. Am Fam Physician 1991 Nov;44(5):1651-1658.(Review)

Werbach MR. Foundations of Nutritional Medicine. Tarzana, CA: Third Line Press, 1997. (Review)

Westermarck T. Selenium content of tissues in Finnish infants and adults with various diseases, and studies on the effects of selenium supplementation in neuronal ceroid lipofuscinosis patients. Acta Pharmacol Toxicol (Copenh). 1977 Aug;41(2):121-128.

Yoshizawa K, Willett WC, Morris SJ, Stampfer MJ, Spiegelman D, Rimm EB, Giovannucci E. Study of prediagnostic selenium levels in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst 1998 Aug 19;90(16):1219-1224.
Abstract: BACKGROUND: In a recent randomized intervention trial, the risk of prostate cancer for men receiving a daily supplement of 200 microg selenium was one third of that for men receiving placebo. By use of a nested case-control design within a prospective study, i.e., the Health Professionals Follow-Up Study, we investigated the association between risk of prostate cancer and prediagnostic level of selenium in toenails, a measure of long-term selenium intake. METHODS: In 1986, 51,529 male health professionals aged 40-75 years responded to a mailed questionnaire to form the prospective study. In 1987, 33,737 cohort members provided toenail clippings. In 1988, 1990, 1992, and 1994, follow-up questionnaires were mailed. From 1989 through 1994, 181 new cases of advanced prostate cancer were reported. Case and control subjects were matched by age, smoking status, and month of toenail return. Selenium levels were determined by neutron activation. All P values are two-sided. RESULTS: The selenium level in toenails varied substantially among men, with quintile medians ranging from 0.66 to 1.14 microg/g for control subjects. When matched case-control data were analyzed, higher selenium levels were associated with a reduced risk of advanced prostate cancer (odds ratio [OR] for comparison of highest to lowest quintile = 0.49; 95% confidence interval [CI] = 0.25-0.96; P for trend = .11). After additionally controlling for family history of prostate cancer, body mass index, calcium intake, lycopene intake, saturated fat intake, vasectomy, and geographical region, the OR was 0.35 (95% CI = 0.16-0.78; P for trend = .03). CONCLUSIONS: Our results support earlier findings that higher selenium intakes may reduce the risk of prostate cancer. Further prospective studies and randomized trials of this relationship should be conducted.

Yu MW, Horng IS, Hsu KH, Chiang YC, Liaw YF, Chen CJ. Plasma selenium levels and risk of hepatocellular carcinoma among men with chronic hepatitis virus infection. Am J Epidemiol. 1999 Aug 15;150(4):367-374.
Abstract: Both experimental and epidemiologic studies have linked a low dietary intake of selenium with an increased risk of cancer. The authors examined the association between plasma selenium levels and risk of hepatocellular carcinoma (HCC) among chronic carriers of hepatitis B and/or C virus in a cohort of 7,342 men in Taiwan who were recruited by personal interview and blood draw during 1988-1992. After these men were followed up for an average of 5.3 years, selenium levels in the stored plasma were measured by using hydride atomic absorption spectrometry for 69 incident HCC cases who were positive for hepatitis B surface antigen (HBsAg) and/or antibodies against hepatitis C virus (mostly HBsAg positive) and 139 matched, healthy controls who were HBsAg positive. Mean selenium levels were significantly lower in the HCC cases than in the HBsAg-positive controls (p = 0.01). Adjusted odds ratios of HCC for subjects in increasing quintiles of plasma selenium were 1.00, 0.52, 0.32, 0.19, and 0.62, respectively. The inverse association between plasma selenium levels and HCC was most striking among cigarette smokers and among subjects with low plasma levels of retinol or various carotenoids. There was no clear evidence for an interaction between selenium and alpha-tocopherol in relation to HCC risk.

Yu SY, Li WG, Zhu YJ, Yu WP, Hou C. Chemoprevention trial of human hepatitis with selenium supplementation in China. Biol Trace Element Res 1989 Apr-May;20(1-2):15-22.
Abstract: A three-year study has been conducted for prevention of infectious hepatitis with supplementation of table salt fortified with 15 ppm anhydrous sodium selenite to the general population of 20,847 persons in a township M.Z. at Qidong County, Jiangsu Province, China. The results showed that the incidence of virus hepatitis infection in the test township was significantly lower than that of controls provided with normal table salt. The incidence rate of infectious hepatitis in the treated township M.Z. was 1.20 and 4.52 per 1,000, whereas the average incidence in the 6 surrounding control townships was 2.96 and 10.48 per 1,000 in 1986 and 1987, respectively. The incidence of hepatitis B surface antigen (HBsAg+) was 13.2% vs 19.23% for males and 10.42% vs 12.24% for females in the supplemented vs nonsupplemented neighboring township, respectively. Epidemiological studies have demonstrated that a low grain Se content is associated with a high regional incidence of hepatitis B virus infections.

Yu SY, Zhu YJ, Li WG. Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol Trace Elem Res. 1997 Jan;56(1):117-124.
Abstract: High rates of hepatitis B virus (HBV) infection and primary liver cancer (PLC) are present in Qidong county. Epidemiological surveys demonstrated an inverse association between selenium (Se) level and regional cancer incidence, as well as HBV infection. Four-year animal studies showed that dietary supplement of Se reduced the HBV infection by 77.2% and liver precancerous lesion by 75.8% of ducks, caused by exposure to natural environmental etiologic factors. An intervention trial was undertaken among the general population of 130,471. Individuals in five townships were involved for observation of the preventive effect of Se. The 8-yr follow-up data showed reduced PLC incidence by 35.1% in selenized table salt supplemented vs the nonsupplemented population. On withdrawal of Se from the treated group, PLC incidence rate began to increase. However, the inhibitory response to HBV was sustained during the 3-yr cessation of treatment. The clinical study among 226 Hepatitis B Surface Antigen (HBsAg)-positive persons provided either 200 micrograms of Se in the form of selenized yeast tablet or an identical placebo of yeast tablet daily for 4 yr showed that 7 of 113 subjects were diagnosed as having PLC in the placebo group, whereas no incidence of PLC was found in 113 subjects supplemented with Se. Again on cessation of treatment, PLC developed at a rate comparable to that in the control group, demonstrating that a continuous intake of Se is essential to sustain the chemopreventive effect.