Selenium
Nutrient Name: Selenium.
Elemental Symbol: Se.
Related Substances: Seleocysteine, selenomethionine; selenium aspartate; sodium selenite.
| Drug/Class Interaction Type | Mechanism and Significance | Management | Chemotherapy
 / 
| Selenium, as part of an antioxidant formulation, appears to reduce adverse effects of chemotherapy in treatment of ovarian cancer, most likely by reducing oxidative stress and enhancing activity of glutathione peroxidase system. Further clinical trials warranted.
| Coadministration appears to provide benefit without impairment of therapeutic efficacy.
| Cisplatin
/
| Selenium can reduce nephrotoxicity and adverse effects on white blood cells associated with cisplatin, apparently without inhibiting antineoplastic activity of cisplatin. Bioactivation of selenite into selenols is a glutathione-dependent process that enables formation of protective cisplatin-selenol complex.
| Coadminister, with supervision and monitoring. High selenium levels required may be toxic. Watch for interference with drug activity.
| Clozapine
| Clozapine may decrease selenium levels; this may contribute to adverse effects associated with the drug, including agranulocytosis, decreased glutathione, and effects on the heart.
| Coadminister selenium at modest levels. Monitor.
| Corticosteroids, oral
| Inflammatory conditions may be associated with low selenium status. High-dose oral corticosteroids increase urinary selenium loss and may lower plasma selenium levels. Selenium enhancement can also support immune function and reduce risk of oxidative DNA damage.
| Coadminister selenium with extended high-dose oral corticosteroid therapy.
| Doxorubicin
/ 
| Selenium may reduce doxorubicin-induced cardiotoxicity without interfering with the drug’s antiproliferative effect, possibly by increasing cardiac mitochondrial glutathione peroxidase activity and reducing myocardial malondialdehyde content. Coadministration, at typical doses, is considered nontoxic and unlikely to interfere with therapeutic action of doxorubicin.
| Selenium may be more effective when given before doxorubicin exposure. Assess cardiac performance during treatment.
| Oral contraceptives (OCs)
/
| OCs may decrease selenium levels. Selenium enhancement might reduce oxidative DNA damage and genomic instability, thereby reducing risk of hormone-associated cancer.
| Coadminister, especially with selenium-deficient diet.
| Valproic acid
/ /
| Valproic acid may decrease plasma selenium levels. Concomitant selenium may enhance antioxidant activity, particularly glutathione peroxidase, and decrease drug-induced toxic effects (e.g., hepatotoxicity) related to oxidative metabolites.
| Coadminister, especially in children.
|
Physiology and Function
Selenium is an essential trace mineral in the human body, even though it was generally considered a toxic element until the 1950s. Dietary intake of selenium largely determines selenium levels in the body, and the mineral is found in variable amounts in some foods depending on its presence in the soil. The various forms of selenium are absorbed differently in the digestive tract and are retained for different durations.L-(+)selenomethionine is most readily absorbed and exhibits a significantly slower whole-body turnover rate, especially compared with inorganic selenite. These metabolic characteristics provide for efficient use of the selenium contained in methionine.
Selenium plays a key role in numerous metabolic pathways, most notably those exerting an antioxidant action. Selenium is metabolized to methylselenium and S-methylselenocysteine, its bioactive metabolites; it then acts at the level of nuclear transcription factors, signal transduction, cell cycle checkpoints, and cellular apoptosis. Selenium also appears to act as a substitute for sulfur in key signaling enzymes such as tyrosine kinase. In the form of selenocysteine, selenium is incorporated into selenoproteins, which play a central role in cellular antioxidant defenses and serve to neutralize free radicals and reduce risk of cancer and cardiovascular disease. In particular, glutathione peroxidase (GSH-Px, GPX), a selenium-dependent enzyme containing four atoms of selenium, recycles glutathione, reducing lipid peroxidation by catalyzing the reduction of peroxides, neutralizing hydrogen peroxide, and providing anti-inflammatory properties. Within several metabolic pathways, selenium acts as a cofactor, sometimes in the form of selenocysteine. Selenium also potentiates the antioxidant effects of vitamin E. Plasma selenium concentrations influence thyroid hormone levels, particularly the conversion of thyroxine (T4) to the more active triiodothyronine (T3), through its effect on the key regulatory enzyme iodothyronine deiodinase; lowered selenium levels are associated with impaired peripheral conversion of T4to T3. Selenium's role in thyroid hormone activation exerts a special role in peripheral tissues. Thioredoxin reductase, a selenium- and NADPH-dependent flavoenzyme, is involved in intracellular reduction of substrates and appears essential to the mineral's anticancer activity. Selenium also participates in immune and detoxification functions by increasing T lymphocytes, enhancing natural killer cell activity, regulating production of immunoglobulin G (IgG) and tumor necrosis factor, and detoxifying heavy metal toxins, including mercury and cadmium.
The effects of selenium deficiency have been brought into focus through epidemiological studies in areas where the soil is particularly lacking in selenium, most notably the Chinese province of Keshan and Finland. Thus, the multifocal myocarditis of Keshan disease provides a stark study of the pathogenesis and pathology of frank selenium deficiency. Elevated rates of cancer in Finland exemplify the strong association between low dietary intake of selenium and increased risk of malignant disease. Diets high in processed foods are similarly depleted of selenium. Numerous studies have documented an association between selenium intake and serum concentrations and the risk and severity of a wide range of cancers. Other symptoms of selenium deficiency include destructive changes to the heart and pancreas, pseudoalbinism, macrocytosis, increased red blood cell (RBC) fragility, immune system dysfunction, myositis, elevated creatine kinase derived from muscles, whitening of the fingernail beds, and a peculiar form of osteoarthropathy known as Kashin-Beck disease.
Known or Potential Therapeutic Uses
Apart from treatment of deficiency patterns, selenium is most widely known and universally respected as a cancer-preventive nutrient. Although not generally considered an antioxidant per se, selenium forms an integral part of the antioxidant system related to the superfamily of antioxidant enzymes that includes glutathione perioxidase (GSH-Px). Selenium's antioxidant role is critical in many ways, but its cytotoxic and antitumor activities cannot be wholly attributable to such properties. Maximal GSH-Px activity requires only minimal amounts of selenium. Significantly higher levels of selenium, approximately 10 times as much, are necessary to reach levels at which this trace element begins to exercise its cancer prevention effects.
Historical/Ethnomedicine Precedent
Selenium has not been used historically as an isolated nutrient.
Possible Uses
Asthma, atherosclerosis, cardiac arrhythmia, cardiomyopathy, cataracts, childhood infectious diseases, colorectal cancer (risk reduction), depression, dermatitis herpetiformis, diabetic retinopathy, Down syndrome, food intolerance, gingivitis, human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) support, hepatitis, heavy metal toxicity, hospital-acquired infections in very-low-birth-weight infants (preventive), hypothyroidism, liver cirrhosis, lung cancer (risk reduction), macular degeneration, Osgood-Schlatter disease, pancreatic insufficiency, Pap smear (abnormal), parenteral nutrition (adjunctive), phenylketonuria (if deficient), prostate cancer (risk reduction), rheumatoid arthritis, retinopathy, surgery preparation/recovery support.
Dietary Sources
Brazil nuts are the single best food source of selenium. Herring, tuna, sardines, calf liver, soybeans, yeast, garlic, and eggs are good sources. Whole grains, especially wheat, can be excellent dietary sources of selenium but provide variable amounts depending on selenium levels in soil where cultivated.
Nutrient Preparations Available
Selenomethionine, selenocysteine, selenium-rich yeast, and selenium aspartate are organic forms of selenium and are preferable. Sodium selenite is the primary inorganic form of selenium and is generally considered less bioavailable.
Dosage Forms Available
Tablet, injection.
Source Materials for Nutrient Preparations
Yeast; organic selenium, selenite.
Dosage Range
Adult
Dietary: Average U.S. daily intake: 100 µg/day.
Supplemental/Maintenance: An adult intake of 100 to 300 µg/day is often recommended, depending on exposure to environmental toxins and individual risk assessment.
Pharmacological/Therapeutic: 50 to 200 µg/day, can be up to 1000 µg/day.
Toxic: Greater than 900 µg/day.
The U.S. National Academy of Sciences recommends that selenium intake not exceed 400 µg daily, unless the higher intake is monitored. Daily intakes of up to 400 to 500 µg daily appear to be safe in healthy adults, although certain increased risks may be associated.
Note: Men apparently require higher levels of selenium intake than women, possibly because stores are lost with ejaculation.
Pediatric (<18 Years)
Pharmacological/Therapeutic: Usual dosage for children: 30 to 150 µg/day, or 1.5 µg per pound of body weight.
Laboratory Values
Blood Glutathione Peroxidase Activity
Blood glutathione peroxidase (GSH-Px) activity is a sensitive assay. The GSH-Px activity of RBCs can be expressed as international units per gram of hemoglobin.
Activity less than 30 IU/g hemoglobin indicates deficiency.
Serum Selenium
- Serum selenium levels are transient.
- Normal range is 0.9-1.9 µmol/L.
Many clinicians consider blood and urinary levels as inadequate indicators of selenium intake and tissue levels.
Overview
Selenium has a narrow margin of safety. Although it is generally considered safe at typical supplement levels of 100 to 200 µg/day; 800 µg/day is probably the highest long-term daily dose that can be taken without the development of toxicity in most people. There are variations in the toxic dose, as with other nutrients, but selenium must be used with caution. Daily dosages exceeding 900 µg have been associated with adverse effects in some individuals. Estimates from cattle and other animals show that the toxic long-term dose is probably closer to 2.4 to 3 mg/day. This would lead to symptoms such as liver, skeletal, and cardiac muscle damage.
General Adverse Effects
High blood levels of selenium can result in a condition called selenosis .
Dosages greater than 1000 µg of selenium daily for an extended period have been associated with toxic signs that include depression, nervousness, emotional instability, lethargy, weight loss, nausea, vomiting, garlic-like breath and sweat, metallic taste in mouth, digestive irritation, peripheral neuropathies, dermatitis, hair loss, loss of teeth, and fingernail damage or loss. Rare cases of thrombocytopenia and hepatorenal dysfunction have been reported.
Signs and symptoms of severe overdose include fever, increased respiratory rate, gastrointestinal (GI) distress, paralysis, myelitis, and, potentially in extreme cases, death.
There have been no reports of death attributed to selenium toxicity in humans; however, fatal overdoses have been reported in livestock. Reports of selenium overdose in humans indicate resolution of adverse effects on cessation of intake.
Limited secondary research suggests that supplemental intake of selenium, 200 µg/day, for 7.7 years (average) may be associated with an increased risk of developing type 2 diabetes mellitus.
Contraindications
Individuals with low thyroid function or iodine deficiency–induced goiter are reported to be at an increased risk of symptom exacerbation with selenium supplementation. Selenium supplementation in individuals with a history of nonmelanoma skin cancer may raise the risk of squamous cell cancer.
High hair selenium levels in children have been associated with learning disabilities and behavioral problems.
Strategic Considerations
The wide-ranging roles of selenium in healthy human physiology and the well-known adverse effects of selenium deficiency warrant our attention as a valuable agent in health optimization and disease prevention, as well as a potentially critical ally in disease management using conventional pharmacology. In particular, clinicians must consider the selenium depletion patterns associated with many pathologies and suspected to be aggravated by some pharmacological agents. Selenium’s role in cancer prevention has always suggested to clinicians that it might prove to be of therapeutic benefit as a component of cancer therapy. Although the direct treatment of cancer using selenium within an integrative model is just emerging, the use of selenium coadministration within a chemotherapeutic regimen has been the subject of extensive, but still often inconclusive, research. It has been widely demonstrated that alterations in selenium levels directly affect the concentration and activity of glutathione peroxidases. Results from animal experiments indicate that selenium compounds, as well as other antioxidant nutrients such as vitamin E, are protective against lethality and other radiation effects, although to a lesser degree than some synthetic protectors. Further, the strong association recognized between selenium deficiency and cardiomyopathy suggests use of this crucial trace mineral in limiting known cardiotoxic effects of medications such as doxorubicin.
Many of the issues discussed reveal a need for human clinical trials, first to ascertain efficacy and then, on confirmation, to flesh out the particulars of integrative care models using the knowledge, skills, and experience of clinicians experienced in both conventional pharmacology and nutritional therapeutics. Researchers may find value in looking to studies such as the Polish clinical trial investigating selenium deficiency and concomitant administration of selenium (200 µg/day) and antioxidant nutrients for 3 months in women with ovarian cancer undergoing multidrug chemotherapy. Selenium nutrient coadministration was associated with significantly increased serum and hair concentrations of selenium and significantly higher activity of GSH-Px. Further, Last et al. retrospectively analyzed total selenium content in 100 sera of patients with aggressive B-cell non-Hodgkin's lymphoma who had received anthracycline-based chemotherapy, radiotherapy, or both. They determined that serum selenium concentration at presentation is a prognostic factor, predicting positively for dose delivery, treatment response, and long-term survival. The authors concluded that selenium supplementation might offer a novel therapeutic strategy in the treatment of aggressive non-Hodgkin's lymphoma.
Evidence:Cisplatin ( cis-diaminedichloroplatinum, CDDP; Platinol, Platinol-AQ), cyclophosphamide (Cytoxan, Endoxana, Neosar, Procytox). Related but evidence lacking for extrapolation: Alkylating agents: Busulfan (Myleran), carboplatin (Paraplatin), chlorambucil (Leukeran), dacarbazine (DIC, DTIC, DTIC-Dome, imidazole carboxamide), ifosfamide (Ifex, Mitoxana), mechlorethamine (Mustargen, nitrogen mustard), melphalan (Alkeran), oxaliplatin (Eloxatin), phenylalanine mustard (Melphalan), pipobroman (Vercyte), streptozocin (Zanosar), temozolomide (Temodar), thiotepa (Thioplex), uracil mustard (uramustine). See also Cisplatin and Doxorubicin | | Beneficial or Supportive Interaction, with Professional Management | | Prevention or Reduction of Drug Adverse Effect |
Probability:
2. ProbableEvidence Base:
PreliminaryEffect and Mechanism of Action
Selenium can reduce oxidative stress and enhance activity of the glutathione peroxidase (GSH-Px) system.
Research
Sieja and Talerczyk found that selenium supplementation positively influences oxidative stress (as evidenced by lowered levels of the oxidative stress marker malondialdehyde), enhances the GSH-Px system, and decreases the morbidity of patients with ovarian cancer undergoing chemotherapy. Their study involved the proprietary formulation Protecton Zellactiv (Smith Kline Beecham, Fink Naturarznei GmbH). In a clinical trial involving 62 patients with ovarian cancer, after standard debulking surgery, all patients were treated with adjuvant cyclophosphamide and cisplatin chemotherapy. Half the patients were randomized to receive, concurrently with the chemotherapy, either the antioxidant formula containing beta-carotene (25,000 IU), vitamin C (200 mg), vitamin E (27 IU), riboflavin (4.5 mg), niacin (45 mg), and selenium (200 µg) or the same formula without selenium, for 3 months. Patients who received both the antioxidant vitamins and the selenium for 3 months were noted to have significant increases in serum selenium concentration, GSH-Px in erythrocytes (RBCs), and white blood cell (WBC) numbers and a decrease of hair loss, flatulence, abdominal pain, weakness, malaise, and loss of appetite.
Nutritional Therapeutics, Clinical Concerns, and Adaptations
The encouraging findings from this small trial support the need for further large, well-designed clinical trials to investigate integrative therapeutic strategies using selenium with and without other antioxidant nutrients (e.g., Protecton Zellactiv) in conjunction with chemotherapeutic agents. Safe and effective implementation of this therapeutic strategy requires close supervision and regular monitoring within the context of integrative care involving health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics.
Cisplatin ( cis-Diaminedichloroplatinum, CDDP; Platinol, Platinol-AQ). Extrapolated, based on similar properties: Carboplatin (Paraplatin), oxaliplatin (Eloxatin). See also Chemotherapy (Cytotoxic Agents). | | Prevention or Reduction of Drug Adverse Effect | | Beneficial or Supportive Interaction, with Professional Management |
Probability:
3. PossibleEvidence Base:
EmergingEffect and Mechanism of Action
Selenium appears capable of playing a protective role in the treatment of cancer patients by reducing the nephrotoxicity and WBC-lowering effects typically encountered as an adverse effect of chemotherapy regimens employing cisplatin. Cisplatin exerts its antitumor activity through an interaction with DNA, which results in the formation of bidentate adducts. An important adverse effect of cisplatin therapy is nephrotoxicity. Cisplatin also causes changes in selenium levels and GSH-Px activities. The protective effect observed with administration of selenium correlates with higher levels of selenium in the kidney (about eight times) and with higher levels of glutathione in the kidney, both compared to tumors. Selenite is metabolized into selenols, specifically into methylselenol and glutathionylselenol; this bioactivation of selenite into selenols is a glutathione-dependent process. Baldew et al. proposed in 1991 that the formation of a cisplatin-selenol complex (from methylselenol) takes place in the kidney, thereby preventing cisplatin from exerting its nephrotoxic activity. Selenium may also bind with platinum and inactivate the antineoplastic platinum coordination complexes in a manner similar to sulfur, with which it shares many chemical properties.
Research
The research team led by Vermeulen and Baldew conducted a number of studies into the interaction between selenium and cisplatin. A paper published in 1988 reported cisplatin-induced changes of selenium levels and GSH-Px activities in blood of testis tumor patients. The next year, in research using rodents, they determined that administration of sodium selenite (2000 µg/kg), 1 hour before cisplatin therapy, greatly reduced the nephrotoxic effects associated with the medication without altering antitumor activity. In 1993 this team reported a reduction of cisplatin nephrotoxicity in rodents after administration of sodium selenite and noted a lack of interaction at the pharmacokinetic level of both compounds. Sodium selenite, in doses protecting against the nephrotoxicity of cisplatin, did not significantly affect areas under the plasma concentration-time curve (AUC) from 0 to 6 hours or the initial plasma half-lives of cisplatin and total platinum in plasma. An animal study by Ohkawa et al. Similarly found that sodium selenite reduced toxicity from cisplatin in mice.
In a randomized controlled trial with 41 subjects, Chinese researchers investigated the effects of Seleno-Kappacarrageenan, a selenium-containing formulation, as an agent for reducing the nephrotoxicity and bone marrow suppression induced by cisplatin. Administration of the selenium compound, at 4000 µg/day, in conjunction with a cisplatin regimen, resulted in significantly reduced kidney damage, significantly elevated peripheral WBC counts, and significantly less required volumes of blood transfusion compared with controls. Even though researchers observed no toxicity attributable to the Seleno-Kappacarrageenan, the dosage of selenium administered in this study would generally be considered as potentially toxic, if given frequently, and only appropriate under expertly supervised conditions.
A study conducted in Finland, a country known for selenium-poor soil, investigated the potential benefits of selenium and vitamin E in conjunction with cytotoxic chemotherapy in the treatment of 41 women with ovarian cancer. The chemotherapy regimen consisted of cisplatin in combination with either doxorubicin and cyclophosphamide or melphalan. The 29 patients administered nutrients were divided into three groups receiving 200 µg/day sodium selenate, 300 mg/day vitamin E, or both. Sodium selenate alone and combined with vitamin E significantly increased the serum selenium levels, but the activity of serum glutathione peroxidase (GSH-Px) increased significantly only in the selenium-treated and vitamin E–treated patients with low initial GSH-Px activity. Sodium selenate alone significantly decreased the capacity of the platelets to produce thromboxane A 2 (which should result in decreased platelet activation); it also increased high-density lipoprotein cholesterol levels and prevented the elevation of creatine kinase typically associated with cytotoxic chemotherapy. The therapeutic benefits of selenium coadministration appeared to be particularly evident in patients with low initial selenium levels.
In a 1997 review article, Olas and Wachowicz concluded that administration of sodium selenite reduces cisplatin toxicity without inhibiting the antineoplastic activity of cisplatin. Nevertheless, some of the potentially efficacious effects of selenium, such as reducing myelosuppression, suggest the potential for interference with the antitumor activity of cisplatin. Further, sodium thiosulfate is routinely used to deactivate cisplatin. Some head and neck cancer protocols infuse cisplatin intra-arterially through a major artery perfusing the tumor, then inject sodium thiosulfate intravenously, to complex with and deactivate the drug once in the venous circulation. Given the interchangeability of selenium and sulfur, this could also apply to selenium, but since selenium's doses are orders of magnitude less than for sulfur, the stoichiometry would argue against selenium having major interference. This proposition deserves to be rigorously tested in well-designed randomized clinical trials with well-matched patient populations that are large enough to detect even modest gains or losses of therapeutic efficacy.
Nutritional Therapeutics, Clinical Concerns, and Adaptations
Although selenium coadministration represents a valuable option for adjunctive use with cisplatin, the selenium dosages used in many of the cited studies represent a potentially toxic dosage level. Administration of selenium during chemotherapy using cisplatin and carboplatin warrants caution. Some of the potentially beneficial actions of selenium, such as reducing myelosuppression, suggest the as-yet unproven potential for interference with the action of platinum chemotherapy agents. Thus, safe and effective implementation of this therapeutic strategy requires close supervision and regular monitoring within the context of integrative care involving health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics. The collective research findings indicate that selenium appears to be most efficacious when administered 1 hour before cisplatin therapy. Selenium dosage, form, and mode of administration should be determined based on the unique and evolving needs of the individual being treated in coordination with the overall therapeutic strategy. Daily dosages in the range of 200 to 600 µg are considered as generally effective and safe over an extended time. Much higher intermittent doses, up to 4 mg, given 1 hour before platinum chemotherapy, appear to be well tolerated, and are unlikely to lead to toxic accumulation of selenium, unless relatively high doses are also chronically administered.
Clozapine (Clozaril). | | Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management |
Probability:
2. ProbableEvidence Base:
PreliminaryEffect and Mechanism of Action
Clozapine use appears to decrease blood levels of selenium and may contribute to drug-related adverse effects, particularly agranulocytosis.
Research
In a cross-sectional pilot study, Linday et al. investigated the possible role of abnormalities in the body's antioxidant defense system in the pathogenesis of clozapine-associated agranulocytosis, an uncommon adverse effect. They observed that plasma selenium levels were lowest in individuals undergoing clozapine therapy or experiencing postclozapine agranulocytosis; plasma GSH-Px levels were also lowest in the postclozapine agranulocytosis group. A subsequent study using a novel in vitro assay technique revealed that clozapine and its stable metabolites are not cytotoxic per se but are bioactivated to cytotoxic metabolites that may play a role in the pathogenesis of clozapine agranulocytosis. They noted that bioactivation of clozapine (and its metabolite demethylclozapine) was accompanied by depletion of intracellular glutathione.
In a 2003 study, researchers gathered random venous blood samples to compare selenium levels in four groups: individuals diagnosed with mood disorder, schizophrenics treated with clozapine, schizophrenics not treated with clozapine, and a healthy control group. They found that selenium concentrations in plasma and RBCs were significantly lower in schizophrenic patients treated with clozapine compared with all other groups. The authors noted that low selenium concentrations in clozapine-treated patients may be important in the pathogenesis of life-threatening cardiac adverse effects associated with clozapine.
Nutritional Therapeutics, Clinical Concerns, and Adaptations
The cumulative evidence indicates that clozapine may deplete selenium and glutathione, and that an association may exist between such status and susceptibility to clozapine-induced agranulocytosis. At this time, there is no conclusive evidence to confirm or negate the need for, or benefit from, selenium administration in individuals undergoing therapy with clozapine or other atypical neuroleptic medications. Given the protective antioxidant function of selenium in general and potentially in prevention of known adverse effects of clozapine, the conservative course of action would be to offer the patient the option of coadministering modest amounts of selenium (e.g., 100-200 µg/day) during clozapine therapy.
Betamethasone (Celestone), cortisone (Cortone), dexamethasone (Decadron), fludrocortisone (Florinef), hydrocortisone (Cortef), methylprednisolone (Medrol) prednisolone (Delta-Cortef, Orapred, Pediapred, Prelone), prednisone (Deltasone, Liquid Pred, Meticorten, Orasone), triamcinolone (Aristocort). | | Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management |
Probability:
2. ProbableEvidence Base:
ConsensusEffect and Mechanism of Action
High-dose oral corticosteroids increase urinary selenium loss and may lower plasma selenium levels. Some clinicians have also noted that individuals with chronic inflammatory conditions tend to have a preexisting compromised selenium status that would make them particularly susceptible to depletion by steroid medications.
Research
Experimental and clinical studies suggest that selenium modulates inflammatory and immune responses. Low selenium levels are common among individuals with inflammatory rheumatic diseases, although such status does not correlate with disease severity. Peretz et al. studied the plasma selenium levels, erythrocyte selenium levels, and activity of the selenoenzyme GSH-Px in erythrocytes of patients with rheumatoid arthritis (RA) and acute inflammatory arthritis. They determined that sustained oral corticosteroid therapy, particularly at high doses (20-60 mg prednisolone daily), was significantly related to the depressed plasma selenium levels of some patients with RA.
Nutritional Therapeutics, Clinical Concerns, and Adaptations
Chronically low selenium levels are associated with diverse pathologies characterized by inflammation and immune dysfunction, including rheumatic disorders. Deficiency of this trace mineral may lead to oxidative DNA damage. The use of corticosteroid medications may further compromise selenium status in some treated individuals. Prevention of marginal selenium deficiency or reversal of steroid-induced depletion by moderate supplementation might enhance host defense mechanisms, facilitate symptom amelioration, and support systemic healing processes. Further research is needed to establish selection criteria and refine methods for ascertainment of appropriate dosage of selenium to obtain the desired stimulatory or inhibitory effect relevant to the disease state and therapeutic strategy. When prescribing glucocorticoid medications and seeking to invoke potential benefits of concomitant selenium, typical therapeutic dosages of selenium are in the range of 100 to 200 µg daily. At this time, no research appears to indicate that concurrent selenium might interfere with the therapeutic action of steroid medications.
Evidence: Doxorubicin (Adriamycin, Rubex). Extrapolated, based on similar properties: Daunorubicin (Cerubidine), epirubicin (Ellence, Pharmorubicin), idarubicin (Idamycin, Zavedos), mitoxantrone (Novantrone, Onkotrone). Similar properties but evidence lacking for extrapolation: Dounorubicin, liposomal (DaunoXome); doxorubicin, pegylated liposomal (Caelyx, Doxil, Myocet). | | Prevention or Reduction of Drug Adverse Effect | | Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management |
Probability:
2. ProbableEvidence Base:
EmergingEffect and Mechanism of Action
Doxorubicin is a highly effective antineoplastic agent, but cardiotoxicity, acute and chronic, is an adverse effect occurring in up to one third of the patients treated after a cumulative dose of 300 mg/m , and increasing sharply beyond a cumulative dose of 360 mg/m . The resultant irreversible and dose-dependent cardiomyopathy limits its clinical usefulness. Doxorubicin's toxicity results in significant part from free-radical generation and the resultant oxidative stress. Selenium significantly reduces toxicity of doxorubicin without reducing its antitumor activity. Although inorganic selenium lacks direct antioxidant properties, the glutathione peroxidases and other circulating selenoproteins play a central role in cellular antioxidant functions. Selenium coadministration with drug delivery, typically as part of an antioxidant combination, can inhibit doxorubicin-induced decreases in myocardial vitamin E and GSH-Px, reduce oxidative stress, and reduce or prevent doxorubicin-induced cardiotoxicity.
Cardiotoxicity of anthracycline chemotherapy agents is multifactorial and also involves oxidative stress partly mediated by an iron-catalyzed Fenton reaction; iron-chelating agents have been shown to decrease doxorubicin cardiac toxicity. Two conditions of cardiotoxicity have been recognized. The first is a dose-independent idiosyncratic phenomenon appearing immediately after anthracycline administration and is based on a pericarditis-myocarditis syndrome in patients without previous cardiac disease. The second condition is dose related and characterized by progressive decline of left ventricular systolic function, as assessed by the ejection fraction on nuclear medicine and echocardiographic studies, which may lead to congestive heart failure (CHF). Diastolic dysfunction may also lead to CHF, with or without concomitant compromise of left ventricular ejection fraction. On pathological examination, progressive anthracycline-related cardiac damage may include restrictive endomyocardial disease, characterized by fibrous thickening of the endomyocardium, and dilated cardiomyopathy, as a result of myocardial fibrosis and hypertrophy of surviving myocytes. Symptoms can appear many years after completion of chemotherapy, although sequential assessment of left ventricular systolic and diastolic function will show compromise long before symptomatic CHF ensues. Risk of anthracycline-induced CHF is increased by radiotherapy fields that involve all or part of the heart.
Cardiac toxicity is similar between equipotent doses of doxorubicin and daunorubicin, slightly lower for epirubicin, and only one-sixth that of doxorubicin for equipotent doses of mitoxantrone. Doxil and DaunoXome (liposomal doxorubicin and daunorubicin, respectively) have negligible cardiotoxicity, presumably because of minimal cardiac exposure to the active drug with the pharmacokinetics of the liposome-encapsulated preparation.
Research
Within conventional oncology, the anthracycline antibiotic doxorubicin (Adriamycin) is considered one of the most effective chemotherapeutic agents against a variety of cancers, but its utility is seriously curtailed by its cardiotoxic action and the attendant risk of developing cardiomyopathy and heart failure. Studies investigating the possible beneficial role of selenium in relation to doxorubicin toxicity have focused on two issues: selenium deficiency in laboratory animals and the effects of selenium administration in several experimental models.
Most authors, but not all, have reported that in rats, selenium deficiency contributes to an aggravation of doxorubicin cardiotoxicity. In these animal studies, researchers mainly reported that toxic effects in selenium-deficient rats resulted from the effect of lipid peroxidation or free-radical generation on several direct or indirect mechanisms, including DNA oxidative damage and mitochondrial alterations.
Studies on selenium supplementation have focused on its anticancer effects or its effects on the cardiotoxicity of doxorubicin. In the latter regard, conclusions have varied in several animal models. Van Vleet et al. failed to find any significant evidence of cardioprotection after injecting dogs with selenium during a course of doxorubicin. In a study using mice, Hermansen and Wassermann reported that selenium provided no significant protection against toxic effects from intraperitoneal injections of doxorubicin. Researchers in other animal studies reported that selenium administration provided cardioprotective effects against doxorubicin-induced toxicity. Van Vleet and Ferrans injected rabbits with both doxorubicin and selenium once a week for 17 weeks and found that rabbits thus treated with selenium showed improved survival rates and reduced symptoms of cardiomyopathy. Van Vleet et al. described positive outcomes, including delayed onset of leukopenia and prolonged survival, after selenium was administered to pigs receiving doxorubicin for 13 weeks. Dimitrov et al. found that selenium abrogated doxorubicin-induced cardiotoxicity in rabbits without interfering with the drug's antiproliferative effect. Examination of animals that had received selenium showed increased selenium levels in the plasma and the heart muscle, as well as preservation of normal heart histology. Finally, Boucher et al. demonstrated several positive responses indicating reduction in doxorubicin cardiotoxicity after treating rats injected with intraperitoneal doxorubicin, twice weekly for 3 weeks, with 3 weeks of oral selenium, using standard food enriched with 2500 µg selenium/kg. The animals given selenium showed significantly increased levels of cardiac mitochondrial GSH-Px activity, reduced myocardial malondialdehyde content, and no increase in the degree of structural alterations to sarcomeres induced by doxorubicin.
These mixed results may reveal more about variable responses to doxorubicin and selenium among different species, as well as the influence of different dosages, treatment lengths, and delivery forms of selenium, than about the anticancer or cardioprotective effects of selenium. Generally, selenium was more effective when given before doxorubicin exposure.
In an in vitro study, Vadgama et al. investigated the effects of administering doxorubicin and selenium together to several tumor cell lines. They reported that selenium increased the doxorubicin effect in most of the cell lines, including increased levels of apoptosis and decreased DNA synthesis.
Nutritional Therapeutics, Clinical Concerns, and Adaptations
In considering the paramount issue of doxorubicin-induced cardiotoxicity, the parameters of the individual patient's health status, risk factors, prognosis, and therapeutic preferences must be weighed within a process of informed decision making. Safe and effective implementation of this therapeutic strategy requires close supervision and regular monitoring within the context of integrative care involving health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics. Cardiac performance must be assessed before doxorubicin therapy begins, during treatment, and as part of regular follow-up after chemotherapy has concluded. The animal studies reviewed indicate that pretreatment selenium was more effective in limiting doxorubicin toxicity. Selenium dosage, form, and mode of administration need to be determined based on the unique and evolving needs of the individual being treated, in coordination with the overall therapeutic strategy. Daily dosages in the range of 200 to 600 µg are considered as generally effective and safe over an extended period. A conservative approach to clinical management suggests that selenium administration may provide protective influences and assist the therapeutic process, with little or no known risk that such nutrient coadministration might be toxic or interfere with the pharmacological action of the primary treatment.
Ethinyl estradiol and desogestrel (Desogen, Ortho-TriCyclen). Ethinyl estradiol and ethynodiol (Demulen 1/35, Demulen 1/50, Nelulen 1/25, Nelulen 1/50, Zovia). Ethinyl estradiol and levonorgestrel (Alesse, Levlen, Levlite, Levora 0.15/30, Nordette, Tri-Levlen, Triphasil, Trivora). Ethinyl estradiol and norethindrone/norethisterone (Brevicon, Estrostep, Genora 1/35, GenCept 1/35, Jenest-28, Loestrin 1.5/30, Loestrin1/20, Modicon, Necon 1/25, Necon 10/11, Necon 0.5/30, Necon 1/50, Nelova 1/35, Nelova 10/11, Norinyl 1/35, Norlestin 1/50, Ortho Novum 1/35, Ortho Novum 10/11, Ortho Novum 7/7/7, Ovcon-35, Ovcon-50, Tri-Norinyl, Trinovum). Ethinyl estradiol and norgestrel (Lo/Ovral, Ovral). Mestranol and norethindrone (Genora 1/50, Nelova 1/50, Norethin 1/50, Ortho-Novum 1/50). Related, internal application: Etonogestrel/ethinyl estradiol vaginal ring (Nuvaring). | | Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management | | Drug-induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management |
Probability:
3. PossibleEvidence Base:
EmergingEffect and Mechanism of Action
Human research indicates that oral contraceptives (OCs) are associated with decreased serum selenium concentrations, possibly attributable to interference with selenium absorption.
Research
Heese et al. conducted a study in South Africa involving 200 female students, half of whom had been taking a low-dosage triphasic OC for a minimum of 3 months; the others were using no OCs. Women using OCs demonstrated differences in mean serum selenium concentrations that were statistically significant.
L’Abbe et al. measured the activity of the enzyme glutathione peroxidase (SeGSHPx) as an indicator of selenium status in a large sample of healthy, free-living Canadians. They observed that estrogen use significantly elevated erythrocyte SeGSHPx, non-SeGSHPx, and total activities in both premenopausal and postmenopausal women.
Nutritional Therapeutics, Clinical Concerns, and Adaptations
Although the evidence shows that OCs may be associated with decreased levels of selenium and other micronutrients, the clinical significance of these actions regarding cancer susceptibility and other health risks remains unclear. However, deficiency of this trace mineral may contribute to increased oxidative DNA damage and genomic instability and is considered a significant factor in setting the stage for carcinogenesis. Given the ever-growing literature on the beneficial role of selenium in the prevention of cancer, especially breast cancer, the adverse implications of contraceptive-induced decreases in selenium levels become increasingly significant.
Apart from supplementation of selenium, intake levels primarily depend on the levels of selenium in the soil where foods have been grown. Health care professionals providing care to women using OCs may want to discuss the potential benefits of compensatory selenium intake and present clinical options. Many practitioners experienced in nutritional therapeutics recommend 100 to 200 µg of selenium as the appropriate daily adult dose for cancer prevention; such a dosage level would also be generally considered adequate to address the additional depletion pattern possible from OCs. However, the character of an individual's diet, geographic locale, family history, personal medical history and health status, and other aspects of individual susceptibility, particularly pharmacogenomic variability of estrogen sensitivity and liver metabolic processes, need to be considered in determining individual risk severity and the relative need for such nutrient support.
Divalproex semisodium, divalproex sodium (Depakote), sodium valproate (Depacon), valproate semisodium, valproic acid (Depakene, Depakene Syrup). | | Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management | | Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management | | Prevention or Reduction of Drug Adverse Effect |
Probability:
4. PlausibleEvidence Base:
EmergingEffect and Mechanism of Action
Valproic acid (VPA) may decrease plasma selenium levels and interfere with related normal physiological functions based on the medication's expected pharmacological actions. Researchers have produced mixed evidence as to the clinical significance of potential selenium (and glutathione) deficiency and its relative impact for different individuals and within different patient populations. Children undergoing anticonvulsant therapy using VPA may be particularly vulnerable to the hepatotoxicity and other adverse effects typically associated with the medication. Concomitant selenium intake may prevent or reduce adverse effects experienced by some individuals undergoing VPA therapy, at least in part by countering drug-induced depletion. Selenium-dependent antioxidant activity, particularly involving GSH-Px, appears to play a critical role in protecting against specific oxidative metabolites of VPA associated with the drug's toxicity.
Research
Recent studies suggest that membrane lipid peroxidation may be causally involved in some forms of epilepsy, and that conventional anticonvulsant treatment may adversely affect selenium-dependent antioxidant systems. Although a significant body of evidence demonstrates that VPA adversely impacts selenium and glutathione levels, other researchers have reported minimal depletion of selenium and negligible clinical implications. Research indicates that VPA's cytotoxic activity is the result of generation of hydrogen peroxide and the production of highly reactive hydroxyl free radicals. Buchi et al. found that the free-radical scavenging action of alpha-tocopherol (vitamin E) and N,N′-diphenyl- p-phenylenediamine (DPPD) protected against lipid peroxidation and hepatotoxicity caused by VPA in rats. Conclusive findings from clinical trials specifically investigating the severity or clinical significance of these effects or the appropriate dosage and specific therapeutic benefits of selenium supplementation have yet to be published.
In 1984, Hurd et al. examined several aspects of altered trace-metal status resulting from anticonvulsant therapy using VPA. They found that administering VPA to rats produced a one-third reduction of hepatic selenium and significant reductions of plasma levels of both selenium and zinc. Also, decreased plasma selenium levels characterized patients treated chronically with VPA as their sole anticonvulsant medication. Further, in addressing the disproportionate incidence of hepatotoxicity and other adverse effects among children, these researchers suggested that this “could be due to decreased selenium concentrations when mechanisms for protection against peroxidative damage are not fully developed.”
Several research teams have investigated plasma trace element, plasma GSH-Px, and superoxide dismutase (SOD) levels in epileptic children receiving antiepileptic drug therapy. Kurekci et al. found plasma selenium concentrations (as well as those of copper, zinc, manganese, and magnesium) of patients undergoing valproate (or carbamazepine) monotherapy were not statistically different from those of control subjects, but that plasma GSH-Px activities in the VPA group were higher than in the control group, and the difference was statistically significant. Subsequently, Graf et al. compared antioxidant enzyme activities in 15 children with a history of serious adverse experience (SAE) related to VPA therapy to those of 35 patients with good clinical tolerance of VPA, and 50 healthy, age-matched subjects. In patients who had SAEs, GSH-Px was significantly depressed, and glutathione reductase (GSSG-R) was significantly elevated relative to values for the other groups. Selenium and zinc concentrations were lower in SAE patients than in controls. The authors concluded that individual susceptibility played a critical role in SAEs caused by VPA therapy and that selenium-dependent antioxidant activity appeared to be central to that protective function. In 2002, Verrotti et al. published their findings from a clinical trial of sodium valproate and carbamazepine (CBZ) therapy for 1 year on serum selenium, copper, zinc, GSH-Px, and SOD levels in 36 epileptic children. They reported no initial differences in levels of all parameters studied between controls and epileptic subjects and that, after 1 year of medication, patients treated with VPA and CBZ continued to show normal values.
Conclusive judgments as to the interaction between VPA and selenium await further evidence from human clinical trials. Hepatotoxicity and other adverse effects attributable to VPA appear to be related to a number of known and unknown factors, including, in some measure, diminished antioxidant capacity resulting from depleted selenium and glutathione levels, age-related immaturity of necessary detoxification functions, and individual pharmacogenomic variability in tolerance of VPA and its metabolites.
Nutritional Therapeutics, Clinical Concerns, and Adaptations
Valproic acid, along with other forms of conventional anticonvulsant therapy, is associated with drug-induced nutrient depletion and deficiency patterns adversely affecting a wide range of micronutrients, including selenium. Use of VPA produces numerous adverse effects, especially on the liver, but no conclusive evidence has emerged to demonstrate the clinical role of selenium, or other micronutrients supporting antioxidant and detoxification processes, in countering these adverse effects or in the treatment of the underlying pathology of epilepsy.
Preliminary evidence indicates a potential risk of selenium deficiency associated with VPA in some individuals and groups, even though there may be no consensus as to its prevalence or clinical significance. Inadequate presence of selenium in dietary sources is common, especially in areas where soils are selenium deficient. Whether or not sufficient evidence exists to support use of concomitant selenium in relation to the direct adverse effects of VPA therapy, a general consensus exists that sustained selenium deficiency, and other nutrient depletion patterns, constitute an enhanced and avoidable risk for susceptibility to cancer and other chronic diseases. In particular, selenium deficiency may contribute to increased oxidative DNA damage, and genomic instability is considered a significant factor in setting the stage for carcinogenesis. Thus, administration of selenium at levels of 200 to 400 µg per day, depending on age, weight, and health status, may be beneficial in terms of reducing specific adverse effects caused by anticonvulsant treatment with VPA, as well as broader increased risk factors. Physicians prescribing VPA are advised to discuss the risks, especially adverse effects and potential depletion patterns, associated with VPA treatment and suggest options for supportive nutritional interventions, particularly antioxidants and selenium, or refer to a physician or other health care professional experienced in nutritional therapies.
Bleomycin (Blenoxane).
Recent research indicates that selenium might interfere with the antineoplastic action of bleomycin, an antibiotic used in the treatment of various cancers. Bleomycin is known to damage DNA by free-radical mechanisms. In two rat studies published in 2001, Desai et al. found that selenium may inhibit the therapeutic action of bleomycin, most likely by enhancing the catalytic function of glutathione peroxidase.
Atorvastatin (Lipitor), fluvastatin (Lescol, Lescol XL), lovastatin (Altocor, Altoprev, Mevacor); combination drug: lovastatin and niacin (Advicor); pravastatin (Pravachol), rosuvastatin (Crestor), simvastatin (Zocor); combination drug: simvastatin and extended-release nicotinic acid (Niaspan).
Recent studies suggest that antioxidant nutrients may interfere with the therapeutic action of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, popularly known as statins, particularly simvastatin (Zocor), in combination with niacin. The synergistic interaction between simvastatin and niacin has been shown to be effective in reducing low-density lipoprotein (LDL) cholesterol and increasing high-density lipoprotein (HDL) cholesterol levels in individuals with hyperlipidemia, particularly in the context of personal history of cardiac events, malignant family history of heart disease, elevated inflammatory index markers (IIMs), or other high-risk factors. At this point, evidence from clinical trials, particularly two papers published in 2001 by Cheung, Brown, et al. at the University of Washington, suggests that coadministration of antioxidants (including selenium) may diminish this combination medication's effectiveness in elevating HDL cholesterol. However, evidence thus far indicates that the interaction observed was between one or more of the antioxidants used and niacin, rather than involving the statin agent directly. Furthermore, no evidence has emerged to indicate that selenium in particular is responsible for this putative undesirable effect.
The toxicity of selenium at high dosages, especially in its inorganic forms, is largely attributable to its depletion of SAMe reserves. SAMe is the body's principal methyl donor, and the metabolism of inorganic selenium requires both extra methyl donors and higher levels of antioxidants on its way to becoming methylselenol.
Numerous researchers and clinicians have reported deficiency and depletion patterns involving a wide range of micronutrients, particularly trace elements, in patients receiving TPN, especially over extended periods. Selenium can prevent adverse effects, particularly cardiomyopathy. A 1997 German review concluded: “The dietary parenteral selenium requirement can be calculated on the basis of the maximal gene expression of the selenoprotein plasma glutathione peroxidase (plGPx). In total parenteral nutrition a daily requirement of 0.01 µmol/Kg body weight for adults and 0.025 µmol/Kg body weight for children can be seen as adequate and safe.” Similarly, a 1996 Japanese review of the subject concluded: “Requirement of trace elements for human adults from TPN estimated as follows. Zinc: 3-4 mg/day, copper: 0.02-0.05 mg/day, iron: 1-2 mg/day, manganese: 0.15-0.80 mg/day, selenium: 0.02-0.05 mg/day, chromium: 0.01-0.015 mg/day, molybdenum: 0.075-0.250 mg/day and iodine: 0.070-0.140 mg/day.”
Selenium potentiates the antioxidant activity of vitamin E. Selenium and vitamin E act synergistically and are more effective when taken together.
Berkson reported that symptomatic hepatitis C patients with elevated transaminases who were placed on a “conservative triple antioxidant” therapy comprising alpha lipoic acid, selenium, and Silybum marianum(milk thistle) were spared hepatic transplantation, showed improved laboratory indices, and returned to normal working life. Multi-antioxidant therapy combining alpha lipoic acid with other antioxidant agents, such as selenium and the herb milk thistle, is synergistic in hepatitis C therapy and may provide a cost-effective alternative approach, even in individuals with a poor prognosis.
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