BIOCHEM 612
Chromium and Selenium
metabolism and their Toxic effects

INTRODUCTION
• Chromium is an essential trace mineral widely distributed
throughout the body.
• Chromium is a micronutrient found in several oxidation
states, being trivalent chromium and hexavalent chromium
Dietary sources of chromium include
 Whole grain products
 Green beans
 Broccoli
RDA
35pg/day for men and 25pg/day for women.

• Blood level: Serum level of chromium in
normal healthy adult is about 6 to 20 μg/100
ml.
Requirements: Recommended daily
requirement for an adult is approximately 50–
200 μg/day.

METBOLISM
• Cr is believed to be absorbed from the SMALL
INTESTINE by passive diffusion.
• Transported from the bloodstream to tissues
by the iron transport protein transferrin.
• Transported from the tissues back to the
bloodstream and ultimately to the urine for
elimination by the peptide low-molecular-
weight chromium-binding peptide (LMWCr).

ABSORPTION
• Trivalent chromium is the type found in food and
supplements and is not toxic.
• Chromium is absorbed poorly in the diet.
• Only 5% of dietary chromium is absorbed.
• Cr3+ is solubilized and complexed with ligands in the
stomach prior to absorption through the small intestine,
especially in the jejunum.
• Mainly absorbed by passive diffusion.
• In cytosol it exists in two forms bounded (with
metalothioneine) and free from which is transported to
blood.
• The homeostasis of free and bounded cellular chromium is
maintained by MBSP (Metal binding stabilizing peptide).

PROMOTERS
• Cr absorption from food is enhanced by the
presence of amino acids, the ascorbic acid,and
high carbohydrate.
INHIBITORS
• Phytates and antacids (natrium hydrogen
carbonate, magnesium hydroxide) reduce Cr
absorption.

Transportation
• Transported in the bloodstream to tissues in
bounded form with transferrin (90%).
• 10% is transported with albumin (loosly
bounded or free form).
• It is transported from the tissues back to the
bloodstream and ultimately to the urine for
elimination by the peptide low-molecular-
weight chromium-binding peptide (LMWCr) or
also known as chromodulin.

CELLULAR UPTAKE AND UTILIZATION
• Insulin dependent (free form)
• Insulin independent (bounded form)

CELLULAR UPTAKE AND UTILIZATION
OF BOUNDED FORM
Insulin independent
• Cellular uptake takes place by transferin receptors TFR.
• After Cr-Tf complex binds to TfR, the complex undergoes
endocytosis to form vesicles.
• The acidic pH inside late endosome (by proton pump ATPase to
pH5.5) causes Cr to dissociate from Tf.
• Tf still remains bound to TfR inside endosome.
• DMT1 present on endosomal membrane transports the free Cr.
• It can bound to metalothioniene in kidney and liver for its
subsequent cellular use or also as chromodulin in other tissues.
• TfR1-apoTf complex is recycled back to cell membrane.
• ApoTf is released from TfR .

CELLULAR UPTAKE AND UTILIZATION
OF FREE FORM
Insulin dependent
 It is triggered in high insulin level in the blood.
 Insulin binds to its insulin receptors it causes conformational
changes in alpha subunits which stimulated movement of
chromium from blood to inside of active cells where it binds to low-
molecular-weight chromium-binding peptide ‘chromodulin’.
 Active chromodulin then binds to beta subunits of insulin receptors
to enhance kinase activity which in turn will enhance glucose
uptake from cell membrane after activation of GLUT4.
 Chromium bonded to chromodulin enhances the response of
insulin receptors and uptake of glucose special in insulin resistant
cells.
 As insulin and glucose levels fall to normal concentration the
LMWCB peptide chromodulin is released from the cell.

REGULATION OF CHROMIUM
HOMEOSTATIC CONDITION
• Regulation takes place by release of cortisol
under low chromium level.
• Under stressor influence, secretion of the
cortisol increases, acting as an insulin
antagonist through increasing blood glucose
concentration.

FUNCTIONS
Chromium plays an important role in carbohydrate, lipid
and protein metabolism.
1. Role in Carbohydrate Metabolism: Chromium is a true potentiator
of insulin and is known as Glucose tolerance factor (GTF).
2. Role in Lipid Metabolism: Chromium supplementation in deficient
diets decreases serum cholesterol levels and preventsdecreases
atheromatous plaque formation in aorta.
3. Role in Protein Metabolism:
• it improves the incorporation of amino acids into heart and muscle
tissue proteins.
4. Role in nucleic acid Metabolism:
• Chromium participates in gene expression by binding to chromatin,
causing an increase in initiation loci and consequently, an increase
in RNA synthesis.
• Chromium protects RNA from heat denaturation.

Chromium toxicity
• The induction of the hexavalent form of Cr is responsible for
oxidative damage of the DNA.
• Cr toxicity caused fragmentation of DNA by generating 8-hydroxy-
dG.
• Hexavalent state of Cr may cause a decline in the fidelity of
replication when given at lesser doses.
• Hexavalent chromium has also been found to interfere with certain
heat shock protein expressions like Hsp90α and Hsp72.
• Cr has been found to directly interconnect and damage the DNA by
causing breakage in strands or adducts formation with them
• It inhibited the synthesis of DNA, generated cross-links
(interstrand). adducts, and oxidized bases in the DNA, causing
considerable damage to the liver tissue.

SELENIUM
• Selenium as an essential trace element for all
species including humans.
• Many positive roles of selenium in human
health has been suggested. However excess
selenium is harmful and produces toxic
manifestations.

Occurrence and Distribution
• Biological forms of selenium which occur in
animal body are selenium analogues of S-
containing amino acids, viz. selenomethionine,
selenocysteine found at a mean concentration of
0.2 μg/g.
• It is widely distributed in all the tissues, highest
concentrations are found in liver, kidneys and
fingernails.
• Muscles, bones, blood and adipose tissues show
a low concentration of selenium.

Source
• Principal source of selenium for the food is
plant material.
richest food sources are:
• Organ meats:
• cereals and grains
• fruits and vegetables

METABOLISM
Selenium metabolism is a systemic process that includes the absorption,
transportation, transformation, and excretion of selenium
ABSORPTION
• Absorption of selenium occurs mainly at the lower end of the small
intestine.
• Selenium is obtained in organic forms (SeMet and Sec) and inorganic
forms (selenite and selenate) from diet.
• All forms of selenium, organic as well as inorganic, are readily absorbed.
• Absorption of selenate (Na2SeO4) takes places by a sodium-mediated
carrier transport mechanism.
• Selenite (Na2SeO3 ) is absorbed by passive diffusion.
• Both forms of inorganic selenium compete with organic selenium for
absorption.
• Organic form (selenomethionine) is absorbed using the Amino acid
transporter (ASCT2) enzyme transport system as does methionine.

TRANSPORT
• Absorbed selenium is, Initially reduced within
the erythrocytes to selenide (involves the
enzyme glutathione reductase ) and
transported in the blood mainly bound to ß-
lipoprotein protein.

UPTAKE AND UTILIZATION
• Selenium is taken up by the liver.
• Selenium plays biological roles predominantly
in the form of selenoproteins synthesized by
the selenium metabolic system.

excreted

• The biological functions of selenium are mostly exerted through
selenoprotein domains that contain Sec residues.
• Twenty-five selenoprotein genes have been identified in the human
genome.
• Selenium-responsive genes are the genes whose expression
patterns are influenced by supplementation with selenium or
selenium-containing compounds.
• These responsive genes were closely associated with annotations
related to cell cycle regulation, androgen-responsive genes.
• Selenium supplementation diminished the expression of pro-
inflammatory genes such as cyclooxygenase-2 (COX-2) and tumor
necrosis factor-α (TNF-α). suggesting that selenium has anti-
inflammatory effects on the immune system.

REGULATION
• The expression levels of several
selenoproteins GENES are influenced by the
extent of selenium uptake.
• The selenoprotein GENE expression is more
apparent when the intracellular level of
selenium is limited.

Active under low
selenium
High concentration of
selenium inhibits
SEPSECS

Selenium Toxicity
• Organic selenocystine and seleno-cystamine
are converted to selenols (RSeH) in presence
of thiols which also results oxygen free radical
generation.
• Besides free radical formation selenium can
have inhibitory effects on thiol proteins, for
instance those which have antioxidant affects.

• Selenium toxicosis causes
DNA damage by generating
8-hydroxyguanosine DNA
adducts.
• As an effect of the oxidative
stress, lipid peroxidation
membranes (e.g. cell-
organelle membranes) loose
their integrity thus
lysosomal enzymes can leak
out of them causing serious
necrotic damage in tissues.

CLASS ACTIVITIES
• What is pharmaceu-tical application of selenium
compounds ?
• What is the organ that is affected the most due to
selenium toxicity?
• Selenocysteine is endcoded by the codon?
• Selenium is cofactor of which enzyme?
• Homeostasis of free and bounded cellular chromium is
maintained by which protein?
• What is chromodulin?
• What are the types of chromium uptake mechanisms?
• What is DNA adduct?

Suggested Readings
• Miklós Mézes*, Krisztián Balogh. Prooxidant
mechanisms of selenium toxicity – a review.
Volume 53(Suppl.1): 2009Acta Biologica
Szegediensis.
• MN Chatterjea and R.Shinde. Text book of
Medical biochemistry. Eighth Edition, 2013.