Transcript Lecture 11 Interactions

Potassium in a Nutshell
Mineral Mineral
Interactions
Rule: Seldom will one mineral function in
isolation apart from other minerals
The negative interaction of metal ions is one of
the major dietary factors that causes low
bioavailability of these nutrients. Interactions of
nutritional significance include sodiumpotassium, calcium-magnesium, manganeseiron, iron-copper, and zinc-copper. These
interactions reach potential importance when the
first metal of each pair listed above is in excess
and the other is at the lower limit of requirement.
The trace element interaction of highest practical
significance in human nutrition is the negative
effect of excess zinc on copper bioavailability.
O’Dell, 1989
Trace elements sharing absorptive pathways
compete for uptake, and imbalances in the
ratios between trace elements (Fe/Zn, Zn/Cu,
Fe/Mn) in formulas may impair trace element
absorption. These factors need to be taken into
consideration when setting upper limits for trace
elements in formulas
Lonnerdal, 1989
Guidelines for essential trace element
preparations for parenteral use. A statement by
an expert panel. AMA Department of Foods and
Nutrition.
[No authors listed]
PMID: 107339 [PubMed - indexed for MEDLINE]
How do Minerals fit into life?
The two “Inters”
Interlinked
Interdependence
K
Mg
P
I
Cr
Ca
Mineral Mineral Interactions
Macro
Symptom
Comment
Na – K
Hypertension
K reduced hypertension
Ca – P
Skeletal growth
Diet 1.0 – 1.3 considered ideal
because endogenous P is high
Ca – Mg
Soft tissue calcification
High Ca blocks Mg absorption
P – Mg
Growth rate retarded
High P also blocks Mg absorption
No interaction
1s2
1s22s2 [Be]
Ne
(3s2)
1s22s22p1
Mg
K
1s22s22p6[Ne]
Ne (3s23p6) [Ar]
Ar
Ca
(4s2)
P
Na
No interaction
Why do we know so much more
about Ca interactions with other minerals?
7
3.2% Ca, 0.8% P
Guinea Pigs 6
Daily Wt
gain (g) 5
0.9% Ca, 0.8% P
(normal)
4
3
2.5% Ca, 1.7% P
2
1
1 g/kg
2.4 g/kg
4.0 g/kg
0
0
Mg
K
Ca
P
30
60
120 180 240 360 600 1200
Log of Dietary Mg (mg/100g)
O’Dell and Morris, 1963
Na
=O PO
3
Micro-mineral Interactions
OPO3=
OPO3=
H
H
Fe
Phy-P
Mn
H
=O PO
3
H
=O PO
3
Ca
OPO3=
Phytic Acid (phytate)
Zn
Se
Cu
Mo
I
S
Cu
Mo
S
S
S
S
S
S
Tetrathiomolybdate
Mo
S
S
Human Studies
Zinc Absorption
Iron impedes Zn absorption in human
subjects. Subjects given 12 mg Zn
and the indicated amount of iron in an
aqueous solution.
Copper Absorption
Iron has no significant effect on the
absorption of Cu by human subjects.
Subjects given 3 mg Cu and the
indicated amount of iron in an
aqueous solution.
Iron (mg)
Conclusion: Oral Fe supplements may
impair zinc absorption in a dosedependent manner, but have no effect on
Cu absorption
Troost et al, Am J. Clin Nutr, 2003
Zn –Cu Interactions in Chicks
(O’Dell, 1967)
500
450
Body
Wt.(g)
400
350
300
250
200
150
100
Zn Supl. 28
Cu Supl. --
28
84
84
+
--
+
Mg/Kg
140 140
--
+
Human Studies
Hypocupremia induced by zinc therapy in adults.
Prasad AS, Brewer GJ, Schoomaker EB, Rabbani P.
JAMA 1978 240:2166-2168
Hypocupremia occurred in an adult with sickle cell anemia who
received zinc as an antisickling agent for two years. The
hypocupremia was associated with microcytosis and relative
neutropenia. Administration of copper resulted in an increase in
RBC size and leukocyte counts. We have since observed
hypoceruloplasminemia of varying degrees in several other
sickle cell anemia patients who were receiving oral zinc therapy.
This complication was easily corrected by copper
supplementation.
Phy-P
Fe
Mn
Cu
Se
Ca
Zn
Mo
I
S
Excessive intake of Mn interferes with Fe metabolism. And, excessive
amounts of unbound Fe intracellularly interferes with Mn incorporation
into enzymes.
Implications of Mineral-Mineral Interactions Intracellularly
Dilemma
That certain metals compete with other metals in an antagonistic fashion
raises the question as to how does the correct metal congener and not
the look-alike antagonist find its way into an enzyme?
What effectively eliminates mistakes in metal selection at the level of
protein binding?
Candidates:
Metallochaperones
Effective sequestration
Many metalloproteins can bind diverse metals, but living
cells connect only with their cognate metal cofactor. In
eukaryotes, metal specificity can be achieved through metalspecific metallochaperone proteins.
Yeast Mn superoxide dismutase (SOD2) binds Mn over Fe.
Preference is determined by the relative bioavailability of
these 2 ions within the mitochondria. Normally, most
mitochondrial Fe is unavailable to SOD2. But, when yeast
have mutations in the genes that transport and store Fe, Fe
accumulates in a reactive form that potently competes with
Mn for binding to SOD2, inactivating the enzyme.
Under normal circumstances, a small pool of SOD2-reactive
Fe exists in homeostasis with bound Fe and has access to
SOD2 when mitochondrial Mn is low. Controlling this
reactive Fe pool is critical to maintaining SOD2 activity and
has important potential implications for oxidative stress in
disorders of Fe overload.
Fe Storage
Fe
Fe
Vesicle
transporter
X
FeSOD
MnSOD
Fe
Fe
X
Iron chaperone
MnSOD
Fe
Fe
Fe
Mn
Mn
Fe
Mn
Fe
Phy-P
Fe
Mn
Cu
Se
Ca
Zn
Mo
S
I
Cu/Fe Interactions
Summary of Key Observations:
Yeast cells lacking Cu are unable to transport iron
Iron fed to anemic rats only partially restored
hemoglobin levels in the blood. An ash of alfalfa
resulted in full restoration as did copper salts
Cu deficient animals accumulate stores of iron in
the tissues
Cu deficiency lowers the level of enzymes that oxidize
iron, viz., ceruloplasmin, Fet3 in yeast
Fet3p-Ftr1p in Yeast
Fet3p-Ftr1p high-affinity
Fe-transport (permease) complex
1
3
4
2
1
Fe(III)
Fet3p, a Cu oxidase, couples
with Ftr1p permease at the
Golgi and moves to the plasma
membrane 2 as a functional
complex for Fe(II) uptake.
4 Cu atoms are loaded into Fet3p
by Ccc2p3, a Cu-ATPase. Clions from Gef1p 4 Cl- channel
protein provide the Cl-.
After Labbé and Thiele, 1999
Multicopper Oxidases with Ferroxidase Properties
4Fe2+ + O2 + 4H+
•
•
•
•
•
4Fe3+ + 2H2O
Plasma ceruloplasmin
Membrane-bound ceruloplasmin
Hephaestin
Fet3p
Fet5p
• 200,000 Mwt ceruloplasmin
• 120,000 Mwt ferroxidase in liver
Tissue Iron Accumulation
and Retention in
Aceruloplasminemia
59Fe
Logan et al, 1994
Phy-P
Fe
Mn
Cu
Se
Ca
Zn
Mo
I
S
A slight excess of Cu (or Zn) has no effect on Se
A large excess (100 times) of Cu or Zn has been shown to cause
exudative diathesis in chicks that was corrected by Se supplementation.
Absorption across the intestine is not a factor, but rather internal
distribution of Se to the various organs
Phy-P
Fe
Mn
Cu
Se
Ca
Zn
Mo
I
S
Na2SO4 competes with Na2SeO4, as shown by the SO4
inhibiting the action of the SeO4 in correcting white muscle
disease in lambs.
Puzzling: K2SO4 added to selenomethionine or selenocysteine, the 2
most common dietary sources of Se, did not accentuate the signs of Se
deficiency in lambs.
Selenium Incorporation into Protein
[Se]methionine
Serine
Absorption
ATP
Serine-tRNA
[HSe-PO3]
SeO3
[Se]cysteine-tRNA
[Se]methionine-tRNA
Selenoprotein (GPx, etc)
Assimilation
SO4
[Se]cysteine-tRNA
Ionic radii:
Se = 1.9 nm
S = 2.0 nml
Covalent radii:
Se = 1.03 nm
S = 1.07 nm
[Se]cysteine
Phy-P
Fe
Mn
Cu
Se
Ca
Zn
Mo
I
S
Selenium is required for the enzyme Iodothyronine Selenodeiodinases
Evaluation of influence of selenium, copper, zinc and iron concentrations
on thyroid gland size in school children with normal ioduria
Brzozowska M, Kretowski A, Podkowicz K, Szmitkowski M, Borawska M,
Kinalska I. June, 2006
In spite of proper iodine prophylaxis, there was a 7% rate of goiter
occurrence in school children suggesting factors other than iodine
deficiency influence goiter development. Low concentration of Fe
and/or Se were found in the serum of children with goiter in spite of
their treatment with thyroxine. There may be additional factors
influencing the effectiveness of this treatment.
Iodine and selenium deficiency in school-children in an endemic goiter area in
Turkey.
Aydin K, Kendirci M, Kurtoglu S, Karakucuk EI, Kiris A. 2002
Endemic goiter is one of the most important health problems in Turkey. The
effects of iodine and Se levels on thyroid gland size and thyroid functions is
the objective. Of 73 healthy children 7-12 years old, 38 girls and 35 boys, 32
(43.8%) showed goiter by palpation, 56 (76.7%) by ultrasonography. Serum
T3 and TSH levels were in the upper normal range, and T4 was normal, but
thyroglobulin was higher than normal. Serum Se was 30.84 +/- 23.04
microg/l, and urinary iodine was 3.91 +/- 3.77 microg/dl, appropriate for
moderate iodine and Se deficiency. Thyroid volumes correlated negatively
with Se levels, and not at all with urinary iodine and thyroid hormones. In
conclusion, children in this area had significant goiter problems, probably due
to the iodine as well as Se deficiencies.
Selenium and the Control of Thyroid Hormone Metabolism
Aug 2005, Vol. 15, No. 8 : 841 -853
Josef Köhrle
Thyroid hormone synthesis, metabolism and action require adequate availability of
iodine and Se, which affect homeostasis of thyroid hormone–dependent metabolic
pathways.
The three selenocysteine-containing iodothyronine deiodinases constitute a novel
gene family. Se is retained and deiodinase expression is maintained at near normal
levels in the thyroid gland, brain and other endocrine tissues during Se deficiency,
thus guaranteeing adequate levels of T3 the active thyroid hormone.
While some Se enzymes are impaired in patients with cancer and other
disturbances, Se-dependent deiodinase function might still be adequate. However,
Se status could be responsible for altered thyroid hormone metabolism. Limited or
inadequate supply of iodine and Se leads to complex rearrangements of thyroid
hormone metabolism enabling adaptation to unfavorable conditions