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Manganese Trace Mineral


manganese metabolism is impaired in the Belgrade laboratory rat.
Chua AC; Morgan EH
Department of Physiology' University of Western Australia' Nedlands'
J Comp Physiol [B , 167(5):361-9 1997 Jul
Homozygous Belgrade rats have a hypochromic anaemia due to impaired
iron transport across the cell membrane of immature erythroid cells.
This study aimed at investigating whether there are also abnormalities
of Mn metabolism in erythroid and other types of cells. The experiments
were performed with homozygous (b/b) and heterozygous (+/b) Belgrade
rats and Wistar rats and included measurements of Mn uptake by
reticulocytes in vitro' Mn absorption from in situ closed loops of the
duodenum' and plasma clearance and uptake by several organs after
intravenous inJection of radioactive Mn bound to transferrin (Tf) or
mixed with serum. Similar measurements were made with 59Fe-labelled Fe
in several of the experiments. Mn uptake by reticulocytes and
absorption from the duodenum was impaired in b/b rats compared with +/b
or Wistar rats. The plasma clearance of Mn-Tf was much slower than
Mn-serum' but both were faster than the clearance of Fe-Tf. Uptake of
54Mn by the kidneys' brain and femurs was less in b/b than Wistar or
/+b rats' but uptake by the liver was greater in b/n rats. Similar
differences were found for 59Fe uptake by kidneys' brain and femurs but
is concluded that the genetic abnormality present in b/b rats affects
Mn metabolism as well as Fe metabolism and that Mn and Fe share similar
transport mechanisms in the cells of erythroid tissue' duodenal mucosa'
kidney and blood-brain barrier.

The effect of manganese supply on thyroid hormone metabolism in the
offspring of manganese-depleted dams.
Eder K; Kralik A; Kirchgessner M
Institute of Nutrition Physiology' Technical University Munich'
Freising' Germany.
Biol Trace Elem Res, 55(1-2):137-45 1996 Oct-Nov
The present study was performed to investigate the effect of manganese
(Mn) supply on metabolism of thyroid hormones in the rat. A study with
rats was carried out over two generations. Female rats were raised with
a Mn-deficient diet (0.1 mg Mn/kg)' and mated to produce a second
generation. The male rats of the second generation were used as
subJects for the investigation. They were divided into five groups and
fed diets with Mn concentrations of 0.1' 0.5' 2.2' 10' and 46 mg/kg for
40 d. For assessment of thyroid hormone metabolism' concentrations of
thyroid hormones in serum and activity of hepatic type I 5`deiodinase
(5`D-1) were measured. Feeding diets with 0.1 mg Mn/kg impaired growth
and food conversion' influenced parameters of thyroid hormone
metabolism' and changed some clinical-chemical parameters' such as
concentrations of total protein' albumin' calcium (Ca) and magnesium
(Mg) as well as activity of alkaline phosphatase in serum. Regarding
the thyroid hormone metabolism' rats fed the diet with a Mn level of
0.1 mg/kg had a higher 5`D-I activity in liver' and consequently a
higher concentration of triiodothyronine in serum than the rats fed the
other diets. In contrast' the concentrations of total and free
thyroxine were not influenced by the Mn intake. Growth'
clinical-chemical parameters' concentrations of thyroid hormones in
serum' and activity of hepatic 5`D-I were similar in the rats fed diets
with Mn concentrations between 0.5 and 64 mg/kg. The present study
shows that feeding a diet with a very low Mn concentration affects
growth and thyroid hormone metabolism and that a dietary level of 0.5
mg Mn/kg is adequate for growth and thyroid hormone metabolism in the
offspring of Mn-depleted dams.

The effect of heavy metals on neutrophils
Hrycek A; Misiewicz A
II Katedry i Kliniki Chor]ob Wewn,etrznych' Sl,askieJ Akademii
MedyczneJ w Katowicach.
Wiad Lek, 49(7-12):107-11 1996
The influences of some heavy metals i.e. of mercury' zinc' copper'
manganese' nickel and cobalt on metabolic activity and functional
states of human neutrophils were presented. Simultaneously the
pathomechanisms of the observed disturbances were described.

Effect of metal ions on calcifying growth plate cartilage chondrocytes.
Litchfield TM; Ishikawa Y; Wu LNY; Wuthier RE; Sauer GR
University of South Carolina, Department of Chemistry and Biochemistry,
Columbia, South Carolina 29208, USA.
Calcif Tissue Int, 62(4):341-9 1998 Apr
The effects of the trace metals zinc (Zn), manganese (Mn), and cadmium
(Cd) on the metabolism of growth plate chondrocytes was examined using
a mineralizing culture system. Supplementation of serum-free primary
cultures of growth plate chondrocytes with 10-100 mu m Zn resulted in
an increase in cell protein and greatly increased alkaline phosphatase
(AP) activity; however, above 25 mu m Zn mineralization of the cultures
was reduced. The effects of Zn on cellular protein and AP activity were
enhanced by the addition of the albumin to the culture media. Removal
of Zn from basal culture media resulted in recoverable reductions in
cellular protein and AP activities. Cadmium was acutely toxic to
chondrocyte cell cultures at concentrations above 5 mu m. Even at very
low concentrations (0.25 mu m) Cd caused significant reductions in DNA,
cellular protein, and matrix protein synthesis. In contrast, Cd had
negligible effects on AP activity or culture mineralization. manganese
treatment (50 mu m) resulted in reduced levels of proteoglycan, cell
protein, DNA synthesis, and collagen synthesis, although AP specific
activity did not change. At 10 mu m, Mn significantly reduced
mineralization but had only minor influence on other culture
parameters. Both Zn (200 mu m) and Cd (0.1 mu m), but not Mn, induced
the synthesis of metallothionein. The physiological and biochemical
effects of specific metal ions is largely dependent on their
physicochemical properties, especially their ligand affinities.
Knowledge of these properties allows predictions to be made regarding
whether the organic or the mineral phase are most likely to be affected
in a mineralized tissue.

Ultrastructure of retina of manganese-deficient rats.
Gong H; Amemiya T
Department of Ophthalmology' Nagasaki University School of Medicine'
Invest Ophthalmol Vis Sci, 37(10):1967-74 1996 Sep
PURPOSE: To elucidate some biologic functions of manganese in the
retina. METHODS: Three-week-old weanling Wistar Kyoto rats were used.
manganese-deficient rats were fed a manganese-deficient solid diet
containing 0.23 mg manganese/100 g diet and all other nutrients.
Control rats were fed a solid diet with 2.9 mg manganese/100 g diet.
The retinas were examined by electron microscopy in the 12th' 18th' and
30th months of experimentation. RESULTS: There was a statistically
significant decrease in the plasma manganese levels in
manganese-deficient animals compared to controls. In rats fed a
manganese-deficient diet for 12 months' photoreceptor cells showed
karyopyknosis-like changes of nuclei and a decrease in size and number
of outer segments. Rats fed a manganese-deficient diet for 18 months
showed a complete loss of photoreceptor cells' and the inner nuclear
layer nuclei came in direct contact with the retinal pigment
epithelium. Rats with manganese deficiency of 30 months showed invasion
by capillaries and processes of M uller-like cells from the sensory
retina into the retinal pigment epithelium. In the sensory retina' M
uller-like cells proliferated' and neural cells disappeared.
CONCLUSIONS: Because manganese is related to Mn superoxide in the
mitochondrial matrix and to protein and glycogen metabolism' manganese
deficiency may disturb the renewal of photoreceptor outer segment
discs' and the decrease in antioxidant action caused by a lower level
of Mn superoxide dismutase may accelerate the damage to photoreceptor
cells. After neural cell loss' M uller-like cells may proliferate.
manganese appears to be essential for maintaining photoreceptor cells.

Effect of essential trace metal on bone metabolism in the
femoral-metaphyseal tissues of rats with skeletal unloading: comparison
with zinc-chelating dipeptide.
Yamaguchi M; Ehara Y
Laboratory of Endocrinology and Molecular Metabolism' Graduate School
of Nutritional Sciences' University of Shizuoka' 52-1 Yada' Shizuoka
City 422' Japan.
Calcif Tissue Int, 59(1):27-32 1996 Jul
The effect of essential trace metals on bone metabolism was
investigated in the femoral-metaphyseal tissues obtained from
skeletal-unloaded rats. Skeletal unloading was designed by using the
model of hindlimb suspension in rats; the animals were fed for 4 days
with the unloading. Femoral-metaphyseal tissues were cultured for 24
hours in a medium containing either vehicle (control)' nickel'
manganese' cobalt' copper' zinc' or zinc-chelating dipeptide
(beta-alanyl-L-histidinato zinc; AHZ) in the concentration range of
10(-6) to 10(-4) M. Bone biochemical components (alkaline phosphatase
activity' glucose consumption' and DNA content) were significantly
decreased by skeletal unloading. The presence of zinc sulfate or AHZ
(10(-5) and 10(-4) M) caused a significant increase of alkaline
phosphatase activity in the bone tissues from unloaded rats. This
effect was not seen by nickel' manganese' cobalt and copper (10(-6) to
10(-4) M). The culture medium glucose was clearly consumed by the bone
tissues. This consumption was inhibited by nickel' manganese' or copper
(10(-5) and 10(-4) M)' while cobalt' zinc' and AHZ had no effect. DNA
content in the bone tissues from unloaded rats was significantly
increased by all metal compounds (10(-5) M). The effect of AHZ on bone
components was greater than zinc sulfate. The AHZ (10(-5) M)-increased
alkaline phosphatase activity in the bone tissues from unloaded rats
was clearly blocked by the presence of cycloheximide (10(-6) M)'
staurosporine (10(-7) M)' dibucaine (10(-4) M)' or okadaic acid (10(-7)
M). The present study demonstrates that' of various essential trace
metals' zinc compounds have an unique anabolic effect on bone
metabolism in the femoral-metaphyseal tissues of rats with skeletal
unloading. Zinc-chelating dipeptide may stimulate bone protein
synthesis through the mechanism that is involved in protein kinases.

Mutations in PMR1 suppress oxidative damage in yeast cells lacking
superoxide dismutase.
Lapinskas PJ; Cunningham KW; Liu XF; Fink GR; Culotta VC
Department of Environmental Health Sciences' Johns Hopkins University
School of Hygiene and Public Health' Baltimore' Maryland 21205.
Mol Cell Biol, 15(3):1382-8 1995 Mar
Mutants of Saccharomyces cerevisiae lacking a functional SOD1 gene
encoding Cu/Zn superoxide dismutase (SOD) are sensitive to atmospheric
levels of oxygen and are auxotrophic for lysine and methionine when
grown in air. We have previously shown that these defects of
SOD-deficient yeast cells can be overcome through mutations in either
the BSD1 or BSD2 (bypass SOD defects) gene. In this study' the
wild-type allele of BSD1 was cloned by functional complementation and
was physically mapped to the left arm of chromosome VII. BSD1 is
identical to PMR1' encoding a member of the P-type ATPase family that
localizes to the Golgi apparatus. PMR1 is thought to function in
calcium metabolism' and we provide evidence that PMR1 also participates
in the homeostasis of manganese ions. Cells lacking a functional PMR1
gene accumulate elevated levels of intracellular manganese and are also
extremely sensitive to manganese ion toxicity. We demonstrate that
mutations in PMR1 bypass SOD deficiency through a mechanism that
depends on extracellular manganese. Collectively' these findings
indicate that oxidative damage in a eukaryotic cell can be prevented
through alterations in manganese homeostasis.

Resonance Raman spectral properties and stability of manganese
protoporphyrin IX cytochrome b5.
Gruenke LD; Sun J; Loehr TM; Waskell L
Department of Anesthesia and the Liver Center' University of
California' and the Veterans Administration Medical Center' San
Francisco 94121' USA.
Biochemistry, 36(23):7114-25 1997 Jun 10
The structure and stability of cytochrome b5 reconstituted with
manganese protoporphyrin IX instead of iron protoporphyrin IX has been
investigated by resonance Raman spectroscopy and stopped-flow visible
spectroscopy. The resonance Raman spectrum of MnIII cytochrome b5 was
consistent with a high-spin hexacoordinate MnIII protoporphyrin IX
structure that converted to a high-spin pentacoordinate structure at
higher laser power. The resonance Raman spectrum of MnII cytochrome b5
indicated a high-spin pentacoordinate structure which was independent
of laser power. Studies of the binding of MnIII protoporphyrin IX to
apocytochrome b5 indicated that the MnIII-containing porphyrin bound
much less tightly to the protein than did heme. Although the
second-order rate constant at 20 degrees C for the association of heme
with apocytochrome b5 (4.5 x 10(7) M(-1) s(-1)) was estimated to be
only 1 order of magnitude higher than that with Mn protoporphyrin IX
(3.3 x 10(6) M(-1) s(-1))' the dissociation of manganese substituted
cytochrome b5 into the apoprotein and free Mn protoporphyrin IX occurs
with a first-order rate constant of 1.2 x 10(-2) s(-1) at 20 degrees C
while the dissociation of heme from cytochrome b5 at room temperature
occurs 3 orders of magnitude more slowly with a first-order rate
constant of 1.67 x 10(-5) s(-1) [Vergeres' G.' Chen' D. Y.' Wu' F.F.' &
Waskell' L. (1993) Arch. Biochem. Biophys. 305' 231-241 . The
equilibrium dissociation constant for manganese-substituted cytochrome
b5 increased with temperature from 4 nM at 20 degrees C to 14 nM at 37
degrees C. These results suggest that' in the reconstituted cytochrome
P450 metabolizing system' especially in studies done with low protein
concentrations (0.1 microM)' and at elevated temperatures (37 degrees
C)' as much as 30% of the manganese-substituted cytochrome b5 may
dissociate to free Mn-protoporphyrin IX and apocytochrome b5.

Pathogenic mechanisms of the acute porphyric attack: speculative roles
of manganese associated enzymes.
Thunell S; Floderus Y; Harper P; Henrichson A; Lindh U; Marklund S
Porphyria Centre Sweden' S:t G oran Hospital' Stockholm' Sweden.
Cell Mol Biol (Noisy-le-grand), 43(1):1-8 1997 Feb
The significantly increased concentrations of granulocyte manganese in
subJects with AIP may be an indication of overexpression of
manganese-associated enzymes. In this study we present further
observations related to this phenomenon and speculate that this may
provide a rational basis for hypotheses attempting to explain the
pathogenesis of the acute attack of porphyria. Such hypotheses are
advanced with regard to pyruvate carboxylase' mitochondrial superoxide
dismutase and glutamine synthetase' three manganese-dependent enzymes
associated with either ALA-generating or ALA-dependent processes. The
metabolic impacts in acute porphyria of these enzymes would be
functions of the current energy charge of the organism' and would thus
explain the protecting and ameliorating effects of glucose in these
conditions. Although granulocytes from AIP subJects have elevated
manganese concentrations' this did not appear to be associated with
increased activities of two enzymes assayed' pyruvate carboxylase or
mitochondrial superoxide dismutase. However' enzyme activities in white
blood cells do not necessarily represent the levels of catalytic
activity in cell types involved in the phenotypic expression of
porphyria. Thus it proposed that hypotheses along these new lines of
thinking are not flawed by the apparently missing correlations' and
should not be therefore discarded. The possible roles of
manganese-associated enzymes in the mechanisms behind the acute
porphyric attack are discussed in some detail in the paper.

Changes in blood manganese levels during pregnancy in iron supplemented
and non supplemented women.
Tholin K; Sandstr om B; Palm R; Hallmans G
Department of Medicine' Ostersund Hospital' Sweden.
J Trace Elem Med Biol, 9(1):13-7 1995 Mar
Blood manganese levels and iron status indices were determined each
trimester in 66 healthy pregnant women. Twenty-five were randomly
assigned to iron supplementation' 19 to placebo and 22 received dietary
advise aimed at increasing their dietary intake of fibre. Iron
supplemented women had significantly higher levels of blood haemoglobin
compared to the levels of the two other groups' and higher serum
ferritin levels compared to the placebo group. No significant
difference in blood manganese levels was observed among the three
groups of women. There was a significant increase in blood manganese
levels from one trimester to the next' which was slightly more
pronounced in non supplemented women. The median values in the three
trimesters were 154 (range 79-360) nmol/L' 190 (range 98-408) nmol/L'
and 230 (range 133-481) nmol/L' respectively. Pregnancy seems to change
manganese status or otherwise influence manganese metabolism
irrespective of iron status and iron supplementation.

Serum and urinary manganese levels in patients with Parkinson`s
Jim]enez-Jim]enez FJ; Molina JA; Aguilar MV; Arrieta FJ;
Jorge-Santamar]ia A; Cabrera-Valdivia F; Ayuso-Peralta L; Rabasa M;
V]azquez A; Garc]ia-Albea E; et al
Department of Neurology of Hospital Pr]incipe de Asturias' Alcal]a de
Henares' Madrid' Spain.
Acta Neurol Scand, 91(5):317-20 1995 May
To elucidate the possible role of manganese in the risk of developing
Parkinson`s disease (PD)' we compared serum levels of manganese' and
24-h manganese excretion by urine in 29 PD patients and in 27 matched
controls. We also measured chromium and cobalt in the same samples. All
these values did not differ significantly between the groups' they were
not influenced by antiparkinsonian drugs' and they did not correlate
with age' age at onset and duration of the PD' scores of the Unified PD
Rating Scale or the Hoehn & Yahr staging in the PD group. These results
might suggest that serum levels and urinary excretion of manganese are
apparently unrelated to the risk of developing PD.


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