Chromium and Selenium Flashcards
History of selenium
- 1930s- Selenium (Se) thought to be responsible for toxicitiy in cattle eating ‘toxic’ plants.
- 1940s- High dose Se rodent study thought to cause frequency of ‘neoplasms’ in liver
- 1957- Se prevents liver necrosis in rodents (original cancer-forming study not reproducible)
- 1960-1970 Se demonstrated to be nutritionally essential and has anti-carcinogenic activity
- 25 ‘selenoproteins’ currently identified. Se is incorporated into the protein during co-translational synthesis of the target protein as Selenocysteine (Sec)
How does selenium function
via ‘Selenoproteins’
* any protein that includes a selenocysteine (Sec, U, Se-Cys) amino acid residue
Chief Biological Functions of Selenium via ‘Selenoproteins’
- Antioxidant
- Enzymic conversion T4 to T3
Role of selenium as an antioxidant
Redox status regulation
* selenium is a part of the glutathione peroxidase which reduces hydrogen peroxide to water thus preventing oxidative stress
Major Selenoproteins
- Glutathione Peroxidase-1 (GTX-1)
- Glutathione Peroxidase-2 (or GTX-GI)
- Glutathione Peroxidase-3 (GTX-3)
- Phospholipid hydroperoxide Glutathione Peroxidase (or GTX-4)
- Iodothyronine 5’-Deiodinase (DI-1)
Glutathione Peroxidase-1 (GTX-1)
Specific for glutathione (GSH), in most cells and plasma. Not reactive for lipid or sterols. GTX-1 catalyses the following reaction:
* 2 x glutathione + ROOH > glutathione disulphide + ROH + H20
Glutathione Peroxidase-2 (or GTX-GI)
Similar function that of GTX-1, but expression primarily in the intestine
Glutathione Peroxidase-3 (GTX-3)
Similar functions, but found in the kidney and secreted into the plasma
* basis unclear.
Phospholipid hydroperoxide Glutathione Peroxidase (or GTX-
4)
intracellular GPX activity, will reduce phospholipid and cholesterol hydroperoxides (not reduced by GPX-1). GPX-4 has ‘broader’ detoxifying capacity than GPX-1.
* k/o mice for GPX-4 embryonic lethal
Iodothyronine 5’-Deiodinase (DI-1)
Major enzyme (90%) that converts T4 to T3, found primarily in ER of liver and kidney cells.
* DI-2: brain, skin, adipose
* DI-3: fetal liver, CNS, muscle
What does dietary intake of Se depend on?
dependent on enrichment in soil.
* Se is derived primarily from volcanic reactions- hence large variations of enrichment in soil across the continents.
* Goes into air and eventually settles on ground so in plants and in animals; some can also go into water supply
Se in animals and plants
- Se in animal products collects as selenocysteine and Se-proteins (variations due to supplementation of Se to animals)
- Some plants can ‘accumulate’ Se to toxic levels (>mg quantities)
Se bioavailability
Hydrophyllic and highly absorbed (80-90%) efficient
Se excretion
Kidney thought to regulate excretion and liver modulate excretion
Se RDAs
- M/F = 55 ug/d
- ↑ with pregnancy and lactation
Se intake in Canada
~100-150 ug/d
Food sources of Se
Wide variety of foods
* nuts and seeds
* fish, meat, poulty
* grains and cereals
* dairy products
Keshan Disease
Selenium deficiency
Endemic of cardiomyopathy until 1980s, in children younger than. 15 years of age.15 in every thousand affected (normally 1 or 2). All surrounding regions poor in Se- very regionally dependent. Intervention study with Se in 1974- reduced frequency to 5 in 1000. All
but not normalized
* Keshan province of China
Se and TPN
1979- New Zealand case-study. Woman undergoing total parenteral nutrition (TNP). Within 20days TPN, dry flaking skin, after 30days muscle pain and wasting. Se plasma concentration was 9ug/L. Infused with 100ug/day Se, all symptoms gone by 1 week.
Se toxicity
TUL: 400-1000ug/day - Symptoms (Long-term effects) of brittle hair and nails, garlic breath
* >2000ug/day (vomiting, diarrhea, fatigue)
* >grams/day (heart attack, kidney failure, death)
Where might Se toxicity occur?
If no access to clean water; Se in water and food supply makes it difficult because cannot really control this
Se impact on arsenic
Se binds arsenic (negatives binds positives) and can reduce the toxicity of arsenic and arsenic can reduce the toxicity of Se. And once they bind it is excreted. Want to get arsenic out of water but limited resources to do so in some places
* 100-200 million people have drinking water contaminated with Arsenic
Properties of Cr?
- Chromium is an essential trace element
- multiple oxidative states
oxidative states of Cr
- Cr3+ (active): form required for biological processes in humans; essential
- Cr6+: by-product of manufacturing processes
Significance of Cr3+ to Humans
Required for biological processes
* Carbohydrate metabolism
* Lipid metabolism
Cr absorption
Intestinal absorption mechanism remains unclear, no specific transporter identified
Where is Cr concentrated in the body?
Upon absorption, Cr3+ is concentrated into three primary sites: kidney, muscle and liver
How is Cr transported?
Principal carrier protein for chromium is transferrin moving Cr from blood to cellular chromodulin
Describe chromodulin
Low Molecular Weight Chromium Binding Substance
* Cr to its own protein binding factor within cells and serves as active way chromium behaves in the cell
binding capacity of transferrin and chromodulin
- 1 transferrin binds 2 Cr3+
- 1 cellular chromodulin binds 4 Cr3+
What might Cr improve?
insulin signalling
* Cr is transported into cells and binds to chromodulin and helps to regulate the insulin signally cascade by facilitating autophosphorylation of IR and and inhibiting the phosphtyrosine phosphatase
Postulated role of Cr3+
- Activates Tyrosine Kinase
- Enhances Insulin Binding
- Increases Insulin Receptor Number
- Increases B- Cell Sensitivity
- Inhibits Phosphotyrosine Phosphatase
Evidence for how Cr may improve insulin signalling
Cr has impact on obese rats by reducing plasma glucose post meal more efficiently than those without Cr
* normal response in lean either way
Suggested mode of action of Cr with T2D
Supplemental chromium intake → increased insulin sensitivity
* Canadian studies indicate up to 30% of patients with diabetes use complementary alternative management strategies
* Chromium is commonly used to increase glycemic control in this population group
Cr3+ food sources
Estimated Cr 3+ absorption
ranges from 0.4% to 2.5%
* (i.e. 35 ug= 0.1-0.63 ug/day)
Cr3+ DRIs
Uses AIs
* M - 35 ug/d
* F - 25 ug/d
* ↑ with pregnancy/ lactation
Dietary insufficiency of Cr
- Impaired glucose tolerance
- Elevated cholesterol and triglycerides, and decreased HDL concentrations
- Nerve and brain disorders (Have been reported for patients on TPN diets without the inclusion of chromium)
Measuring Cr status
Currently, no biological marker exists to accurately measure chromium status
The most efficacious/bio-available form of supplemental chromium
Several trivalent forms have been studied for their ability to affect glycemic control in people with T2D
* Chromium nicotinate
* Chromium chloride
* Chromium picolinate (CrPic)
What Cr supplement is most studied?
Chromium picolinate (CrPic)
* Most efficiently used form; its chemical structure enables optimal bio-availability
* Virtually all experimental trials using CrPic supplementation for subjects with T2D have demonstrated beneficial effects
What are some improved outcomes seen with CrPic?
13 of 15 clinical studies assessed in a review by Broadhurst et al. indicated significant improvements for at least one outcome measure for glycemic control:
* Reduced blood glucose measures
* Reduced insulin measures
* Reduced glycemic medication requirements
Cr3+ UL
No UL for Cr3+
* Consumption of excess Cr3+ through dietary food sources is highly unlikely
* Supplements – controversial
toxicity case of Cr
Patient consumed 600 ug/day over-the-counter oral chromium picolinate for six weeks to aid in weight reduction and developed renal failure
* not seen in clinical trials
Dietary excess of Cr6+
Classified as a human carcinogen - More about industry and water supply not our natural food supply
* Possibility that Cr3+ is converted to Cr6+ in vivo? Has maybe been shown in animal studies, but unlikely for humans in normal conditions
