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and for releasing long fatty acids. Several different

phospholipases (EC 3.1.1.32) are responsible for

hydrolyzing four different ester bonds in phospho-

lipids. The polyunsaturated fatty acids released from

TG and phospholipids are preferentially oxidized

by lipoxygenase. Lipoxygenase (EC 1.13.11.12) util-

izes atmospheric oxygen to oxidize the cis-1, cis-

4-pentadiene part of (n-6) and (n-3) polyunsaturated

fatty acids (linoleate and linolenate) to hydroperox-

ides and hydroperoxyradicals. Lipoxygenase from

germinating barley is more active toward methyl

linoleate and trilinolein. It is thought that during

steeping, the activity of lipoxygenase decreases and

remains low during germination but rises sharply in

the middle of kilning only to decrease again to a very

low level at the end of kilning.

0030 Inorganic materials also undergo significant

changes in barley during malting. Best elucidated

have been the changes pertaining to phosphates. The

majority of the free phosphate raise occurring during

malting originates from degradation of aleurone phy-

tins, potassium and magnesium salts of phytic acid

(myo-inositol haxaphosphate), by the action of phos-

phatase (EC 3.1.3.26), the enzyme able to hydrolyze

phytic acid. In addition, phosphate is released from

phospholipids, DNA, and RNA by appropriate

hydrolytic enzymes.

0031 Among the numerous and complex phenolic com-

pounds that have been identified in barley, the

most extensively studied have been phenolic acids,

flavanols (such as (þ)-catechin and gallocatechin),

pigments, and condensed tannins derived from cate-

chin. Phenol compounds are important in the brewing

process because of their antioxidant properties,

their astringency, and their tendency to form hazes

in beer. Maltsters sometimes manipulate their content

in malt by application of alkaline steeping, which

removes a portion of phenolics from the grain. Vari-

ous oxidase (EC 1.14.18.1) and peroxidase (EC

1.11.1.7) enzymes are able to act on phenolic sub-

stances, but little is known about their action during

malting. Green malt probably contains oxidases that

catalyze the oxidative polymerization of polyphenols

to tannins.

Chemical Aspects of Kilning

0032When the desired enzyme levels and endosperm

modification have been achieved, the germination is

terminated through kilning, a process in which dry air

of increasing temperature is passed through the green

malt to produce a dry and friable grain product.

Kilning eventually arrests all biochemical reactions,

although appropriate manipulations of time, tem-

perature, and air flow parameters allow survival of

many hydrolytic enzymes needed in the later stages of

the brewing process. Kilning also facilitates forma-

tion of a myriad of color, flavor, and aroma com-

pounds that make malt such a unique product.

Responsible for these phenomena are primarily the

complex Maillard reactions. The malt reducing

sugars and amino compounds (amino acids and com-

pounds containing free amino groups), when exposed

to higher temperatures, react with each other to form

N-substituted glycosylamine, which undergoes a

further reaction called the Amadori rearrangement

to 1-amino-1-deoxy-2-ketose (Figure 8). Chemical

reactions continue taking several possible routes.

Enolization of 1-amino-1-deoxy-2-ketose leads to

the formation of furfurals and hydroxymethylfurfur-

als, which polymerize quickly to melanoidins,

Reducing sugar

Amino acids/

other amino compound

N-substituted

glycosylamine

Amadori

rearrangements

1-Amino-1-deoxy-2-ketose

Reductones

+ Amino acids

Strecker

reaction

Strecker degradation products:

Aldehydes O-, S-, N-containing

heterocyclic compounds

Dehydroreductones

Decomposition products,

e.g., aldehydes, furans,

maltol, isomaltol

+ Amino

compounds

+ Amino

compounds

Furfural

Hydroxymethylfurfurals

Melanoidins

Brown nitrogenous polymers and copolymers

fig0008 Figure 8 Simplified scheme of chemical reactions involved in the formation of flavor and color during the Maillard reactions.

Information compiled from Briggs DE (1998) Malts and Malting. London: Blackie Academic & Professional; and Eskin NA (1990) Bio-

chemistry of Foods London: Academic Press with permission.

3684 MALT/Chemistry of Malting

dark-colored insoluble material containing nitrogen.

Enolization may also lead to the formation of reduc-

tones, which, upon decomposition, yield some flavor

compounds such as maltol, isomaltol, acetyl furan,

and various aldehydes. Degradation of amino acids in

the presence of reductones (the Strecker degradation)

leads eventually to the formation of the major aroma

compounds, the heterocyclic pyrrole, pyridine, pyra-

zine, thiazole, and oxazole.

0033 In addition to the Maillard processes, several other

reactions occurring during kilning may be responsible

for the color and flavor of malt. The polyunsaturated

fatty acids may be partially oxidized, via reactions

catalyzed by lipoxygenase, to various volatile and

nonvolatile aldehydes, alcohols, lactones, and acids,

responsible for usually undesirable odors. Polyphe-

nols may be converted to colored phlobaphenes. In

specialty malts, still other chemical processes may be

required. For instance, the caramelization reactions

occurring when malts are kilned at very high tempera-

tures result in the dark color and unique flavors of

some food malts. The characteristic flavor and aroma

of some lager-type beers are attributed to a high con-

tent of dimethyl sulfide (DMS) formed during careful

kilning of malts rich in nitrogen; DMS is a degrad-

ation product of the sulfonium compound S-methyl-

methionine (Figure 9).

See also: Barley; Beers: History and Types; Biochemistry

of Fermentation; Chemistry of Brewing; Browning:

Nonenzymatic; Starch: Structure, Properties, and

Determination; Sources and Processing

Further Reading

Briggs DE (1992) Barley germination: biochemical changes

and hormonal control. In: Shewry PR (ed.) Barley: Gen-

etics, Biochemistry, Molecular Biology and Biotechnol-

ogy, pp. 369–401. Wallingford, UK: CAB International.

Briggs DE (1998) Malts and Malting. London: Blackie

Academic & Professional.

Briggs DE, Hough JS, Stevens T and Young TW (1981)

Malting and Brewing Science: Volume 1 Malt and

Sweet Wort, 2nd edn. London: Chapman & Hall.

Enari TM and Sopanen T (1986) Mobilisation of endosper-

mal reserves during the germination of barley. Journal of

the Institute of Brewing 92: 25–31.

Eskin NA (1990) Biochemistry of Foods. London: Aca-

demic Press.

Fincher GB (1992) Cell wall metabolism in barley. In:

Shewry PR (ed.) Barley: Genetics, Biochemistry,

Molecular Biology and Biotechnology, pp. 413–

437.Wallingford, UK: CAB International.

Fincher GB and Stone BA (1993) Physiology and biochem-

istry of germination in barley. In: MacGregor AW and

Bhatty RS (eds) Barley Chemistry and Technology,

pp. 247–295. St. Paul, MN: American Association of

Cereal Chemists.

Hill RD and MacGregor AW (1988) Cereal a-amylases in

grain research and technology. In: Pomeranz Y (ed.)

Advances in Cereal Science and Technology, vol. IX,

pp. 217–261. St. Paul, MN: American Association of

Cereal Chemists.

Hudson OP (1986) Malting technology. Journal of the

Institute of Brewing 92: 115–122.

MacGregor EA and MacGregor AW (1987) Studies of

cereal a-amylase using cloned DNA. CRC Critical

Reviews in Biotechnology 5: 129–142.

Palmer GH (1989) Cereals in malting and brewing. In:

Palmer GH (ed.) Cereal Science and Technology, pp.

61–242. Aberdeen, UK: Aberdeen University Press.

Palmer GH and Bathgate GN (1976) Malting and brewing.

In: Pomeranz Y (ed.) Advances in Cereal Science and

Technology, vol. I, pp. 237–324. St. Paul, MN: Ameri-

can Association of Cereal Chemists.

Sebree BR (1997) Biochemistry of malting. Technical Quar-

terly, Association of the Americas Master Brewers 34:

148–151.

Methionine

Methylation

⊕

COOH + OH

Heat

S -methylmethionine (SMM)

in acrospire and rootlets

S + HO CH

CH COOH

Dimethyl sulfide (DMS)

Homoserine

−

fig0009 Figure 9 Formation of dimethyl sulphide during kilning.

MALT/Chemistry of Malting 3685

MANGANESE

C L Keen and S Zidenberg-Cherr, University of

California, Davis, CA, USA

This article is reproduced from Encyclopaedia of Food Science,

Background

0001 The essentiality of manganese was established in

1931 when it was demonstrated that a deficit of it

resulted in poor growth and impaired reproduction in

rodents. It has long been appreciated that a deficiency

of manganese can be a practical problem in the

pig and poultry industry, and it has been suggested

that manganese deficiency may be a problem in

some human populations. Here, the recent literature

related to manganese nutrition, metabolism, and

metabolic function is briefly reviewed. For additional

information, the reader is referred to more compre-

hensive reviews in the bibliography.

Chemical and Physical Properties

0002 Manganese is widely distributed in the biosphere; it

constitutes approximately 0.1% of the earth’s crust

making it the twelfth most abundant element. Man-

ganese is a component of numerous complex minerals

including pyroluosite, rhodochrosite, rhodanite,

braunite, pyrochroite, and manganite. Chemical

forms of manganese in their natural deposits include

oxides, sulfides, carbonates, and silicates. Concentra-

tions of manganese in groundwater normally range

between 1 and 100 mgl

1

, with most values being

below 10 mgl

1

. Typical airborne levels of manganese

(in the absence of excessive pollution) range from

0.05 to 0.10 mgm

3

0003 Manganese is a transition element located in

column 7a on the periodic table. It can exist in 11

oxidation states, ranging from 3toþ7, with the

most common valences being þ2, þ4, and þ7. The

þ2 valence is the predominant form in biological

systems and is the form that is thought to be max-

imally absorbed. The þ4 valence occurs in MnO

and the þ7 valence is found in permanganate.

0004 The solution chemistry of manganese is relatively

simple. The aquo-ion is resistant to oxidation in acidic

or neutral solutions. It does not begin to hydrolyze

until pH 10, and therefore, free Mn

2þ

can be present

in neutral solutions at relatively high concentrations.

Divalent manganese is a d

ion and typically forms

high-spin complexes lacking crystal field stabilization

energies. The above properties as well as the large

ionic radius and small charge-to-radius ratio result in

manganese tending to form weak complexes com-

pared to other first-row divalent ions such as Ni

2þ

and Cu

2þ

. Free Mn

2þ

has a strong isotropic EPR

signal that can be used to determine its concentration

in the low micromolar range. Mn

3þ

is also critical in

biological systems. For example, Mn

3þ

is the oxida-

tive state of manganese in superoxide dismutase, is the

form in which transferrin binds manganese, and is

probably the form of manganese that interacts with

3þ

. Given its smaller ionic radius, the chelation

of Mn

3þ

in biological systems would be predicted to

be more avid than that of Mn

2þ

. Cycling between

3þ

and Mn

2þ

has been suggested to be potentially

deleterious to biological systems since it can generate

free radicals.

Occurrence and Speciation in Foods

0005Manganese concentrations in typical food pro-

ducts range from 0.4 mgg

1

(meat, poultry, fish) to

20 mgg

1

(nuts, cereals, dried fruit). Teas, which are

often listed as an excellent source of manganese, can

contain anywhere from 300 to 900 mgg

1

of the elem-

ent. An important consideration with respect to food

sources of manganese, however, is the extent to

which the manganese is available for absorption.

For example, while tea contains high amounts of the

element, the high content of tannin found in tea binds

manganese and prevents its absorption from the gas-

trointestinal tract. Similarly, while the concentration

of manganese in cereal grains is significant, the high

content of phytates and fiber constituents may bind

manganese, limiting its absorption. Thus, while a

calculation of intake based on nutrient composition

of foods may show that manganese intake is high,

the actual amount of manganese absorbed will

vary among food sources. Similarly, although meat

products contain low concentrations of manganese,

absorption and retention of manganese from them

are high, making them good sources of the element

in the diet. (See Bioavailability of Nutrients; Cereals:

Dietary Importance; Meat: Nutritional Value; Tea:

Chemistry.)

Analysis

0006Although manganese is widely distributed in the

biosphere, it occurs in only trace amounts in animal

tissues. Tissue concentrations of 4–8 mM are

considered high, while serum concentrations can be

3686 MANGANESE

as low as 5 nM. Owing to the high environmental

levels of manganese relative to its concentration in

animal tissues, considerable effort must be made to

minimize contamination of samples during their col-

lection and handling. As a general precaution, all

glassware and plasticware used in the storage or pro-

cessing of samples should be washed in 20% nitric

acid for at least 48 h and then rinsed exhaustively

with distilled double-deionized water. Washed glass-

ware and plasticware should be stored under dust-

free conditions prior to use. To reduce contamination,

tissues containing very low manganese concentra-

tions should be dissected with plastic or quartz knives

rather than steel knives.

0007 The most common analytical methods that can

sensitively measure manganese (18 nmol l

1

) include

neutron-activation analysis, X-ray fluorescence,

proton-induced X-ray emission, inductively coupled

plasma emission, electron paramagnetic resonance

(EPR), and flameless atomic-absorption spectro-

photometry (AAS). Currently, the most common

method employed is flameless AAS. All of these

methods, with the exception of EPR, measure the

total concentration of manganese in the samples.

EPR allows selective measurement of bound vs free

manganese.

Physiological Role

Tissue Concentrations

0008 The average human body contains between 200 and

400 mmol of manganese, which is fairly uniform in

distribution throughout the body. There is relatively

little variation among species with regard to tissue

manganese concentrations. Manganese tends to be

highest in tissues rich in mitochondria; its concentra-

tion in mitochondria is higher than in cytoplasm or

other cell organelles. Hair can accumulate high con-

centrations of manganese, and it has been suggested

that hair manganese concentrations may reflect man-

ganese status. High concentrations of manganese are

normally found in pigmented structures, such as

retina, dark skin, and melanin granules. Bone, liver,

pancreas, and kidney tend to have higher concen-

trations of manganese (20–50 nmol g

1

) than do

other tissues. Concentrations of manganese in brain,

heart, lung, and muscle are typically < 20 nmol g

1

;

blood and serum concentrations are about 200 and

20 nmol l

1

, respectively. Typical milk concentrations

are in the order of 1 mmol l

1

. Bone can account for

up to 25% of total body manganese because of its

mass. Bone manganese concentrations can be raised

or lowered by substantially varying dietary manga-

nese intake, but bone manganese is not thought to be

a readily mobilizable pool. In contrast to the situation

for several other essential trace elements, the fetus

does not accumulate liver manganese before birth,

and fetal concentrations are significantly less than

adult concentrations. This lack of fetal storage can

be attributed to the apparent lack of storage proteins

and the fact that most manganese enzymes are not

expressed prenatally.

Absorption and Transport

0009Absorption of manganese is thought to occur thr-

oughout the small intestine. The efficiency of manga-

nese absorption is relatively low and is not thought to

be under homeostatic control. For adult humans,

manganese absorption has been reported to range

from 2 to 15% when

Mn-labeled test meals are

used and 25% when balance studies are conducted.

Manganese absorption and retention are higher in

neonates than in adults. Data from balance studies

indicate that manganese retention from human milk

and infant formula is elevated during infancy, sug-

gesting that neonates may be particularly susceptible

to manganese toxicosis.

0010The higher retention of manganese in young

animals in relation to adults may reflect an immatur-

ity of manganese excretory pathways. The avid reten-

tion of the small amount of manganese in milk, and

the postnatal changes in its excretory pattern, under-

score the fact that important changes in manganese

metabolism occur during the neonatal period.

0011In experimental animals, high amounts of dietary

calcium, phosphorus, fiber, and phytate have been

shown to increase the requirements for manganese;

such interactions presumably occur via the formation

of insoluble manganese complexes in the intestinal

tract with a concomitant reduction in the soluble

fraction available for absorption. The significance of

these dietary factors with regard to human manga-

nese requirements remains to be clarified. Studies in

avians have demonstrated that high dietary phos-

phorus reduced manganese deposition in bone by

approximately 50%. Given that the average diet of

many individuals may be considered marginal in

manganese, and high in phosphorus, this antagonism

may have important implications for human health.

The low fractional absorption of manganese from soy

formula has been related to its relatively high phytate

content. The mechanism underlying this effect of

soy protein on manganese absorption/retention has

not been fully delineated. (See Calcium: Physiology;

Dietary Fiber: Effects of Fiber on Absorption; Phytic

Acid: Nutritional Impact.)

0012An interaction between iron and manganese has

been demonstrated in several species. Manganese ab-

sorption increases under conditions of iron deficiency

MANGANESE 3687

in both experimental animals and humans, whereas

high amounts of dietary iron can accelerate the devel-

opment of manganese deficiency in some species. The

mechanisms underlying the interactions between iron

and manganese have not been identified; however,

they probably involve either a transport site or a

ligand. (See Iron: Physiology.)

0013 Manganese entering the portal blood from the gas-

trointestinal tract may either remain free or become

associated with a

-macroglobulin, which is subse-

quently taken up by the liver. A small fraction enters

the systemic circulation, where it may become

oxidized to Mn

3þ

and bound to transferrin. Studies

in-vivo suggest that the Mn

3þ

complex forms very

quickly in blood, in contrast to the slow oxidation

of Mn

2þ

-transferrin complex in vitro. Manganese

uptake by the liver has been reported to occur by a

unidirectional, saturable process with the properties

of passive mediated transport. Once entering the liver,

manganese enters one of at least five metabolic pools.

One pool represents manganese taken up by the lyso-

somes, from which it is thought to be transferred

subsequently to the bile canaliculus. The regulation

of manganese is thought to be maintained in part

through biliary excretion of the element; up to 50%

of manganese injected intravenously can be recovered

in the feces within 24 h. A second pool of manganese

is associated with the mitochondria. Mitrochondria

have a large capacity for manganese uptake, and it is

thought that mitochondrial uptake and release of

manganese may be related. A third pool of manganese

is found in the nuclear fraction of the cell; the roles

of nuclear manganese have not been delineated. A

fourth manganese pool is incorporated into newly

synthesized manganese proteins; biological half-lives

for these proteins have not been agreed upon. The

fifth identified intracellular pool of manganese is free

2þ

. It is thought that fluctuations in the free man-

ganese pool may be an important regulator of cellular

metabolic control in a manner analogous to those

for free Ca

2þ

and Mg

2þ

. Consistent with this idea,

several studies in pancreatic islets have shown that

manganese blocks glucose-induced insulin release by

altering cellular calcium fluxes.

0014 The mechanisms by which manganese is transported

to and taken up by extrahepatic tissues have not been

identified. Transferrin is the major manganese-binding

protein in plasma; however, it is not known to what

extent transferrin facilitates the uptake of manganese

by extrahepatic tissue. Manganese uptake by extrahe-

patic tissue does not appear to be increased under

conditions of manganese deficiency, suggesting a lack

of inducible manganese-transport proteins.

0015 Currently, there is limited information concerning

the hormonal regulation of manganese metabolism.

Fluxes in the concentrations of adrenal, pancreatic,

and pituitary–gonadal axis hormones affect tissue

manganese concentrations; however, it is not clear

to what extent hormone-induced changes in tissue

manganese concentrations are due to alterations in

cellular uptake of manganese-activated enzymes or

metalloenzymes.

Biochemical Functions

0016Manganese functions as a constituent of metalloen-

zymes and as an enzyme activator. Manganese-

containing enzymes include arginase, pyruvate

carboxylase, and manganese-superoxide dismutase

(MnSOD). Arginase, the cytosolic enzyme respon-

sible for urea formation, contains 4 mol Mn

2þ

per

mol of enzyme. Although the activity of this enzyme

can be lower in managanese-deficient animals than in

controls, the functional significance of the reduction

has not been defined. With experimental diabetes,

liver and kidney manganese concentrations and argi-

nase activity can be markedly elevated. This manga-

nese effect on arginase has been suggested to be due

to an effect of Mn

2þ

on the conformational properties

of the enzyme with a resultant modification of

arginase activity. Whether this finding implies an

increased manganese requirement for diabetics has

not been determined.

0017Pyruvate carboxylase, the enzyme that catalyzes

the first step of carbohydrate synthesis from pyruvate,

contains 4 mol Mn

2þ

per mol enzyme. Although the

activity of this enzyme can be lower in manganese-

deficient animals than in controls, gluconeogenesis is

not markedly inhibited in deficient animals.

0018MnSOD catalyzes the disproportionation of O



to H

and O

. The activity of MnSOD in tissues of

manganese-deficient rats can be significantly lower

than in controls. That this reduction is functionally

significant is suggested by the observation of higher

than normal levels of hepatic mitochondrial lipid per-

oxidation in deficient rats. Tissue MnSOD activity

can be increased by several diverse stressors including

alcohol, ozone, interleukin-1, and tumor necrosis

factor-a, presumably as a consequence of stressor-

associated increases in cellular free radical (or

oxidized target(s)) concentrations. The increase in

MnSOD activity can be attenuated in manganese-

deficient animals, potentially increasing their sensitiv-

ity to these insults.

0019For manganese-activated reactions, the metal can

act by binding either to the substrate (such as ATP)

or directly to the protein, resulting in conforma-

tional changes. In contrast to the relatively few man-

ganese metalloenzymes, there are a large number of

manganese-activated enzymes, including hydrolases,

kinases, decarboxylases, and transferases. Many of

3688 MANGANESE

these metal activations are nonspecific in that other

metal ions, particularly Mg

2þ

, can replace Mn

2þ

.An

exception to the nonspecific manganese activation

of enzymes is the manganese-specific activation of

glycosyltransferases. Several manganese deficiency-

induced pathologies have been attributed to a low

activity of this enzyme class. A second example of

an enzyme that may be specifically activated by man-

ganese is phosphoenolpyruvate carboxykinase; low

activities of this enzyme can occur in manganese-

deficient animals.

0020 A third example of a manganese-activated enzyme

is glutamine synthetase. This enzyme, found in high

concentrations in the brain, catalyzes the reaction

þglutamate þATP !glutamine þADP þPi. It

can be speculated that a manganese deficiency-

induced reduction in its activity could help to explain

some of the behavioral defects associated with man-

ganese deficiency. It should be noted that this enzyme

can be inactivated by oxygen radicals; thus, a manga-

nese deficiency-induced reduction in MnSOD activity

theoretically could act to further depress the activity

of glutamine synthetase.

Manganese Deficiency

0021 Manganese deficiency has been demonstrated in sev-

eral species, including rats, mice, pigs, and cattle.

Signs of manganese deficiency include impaired

growth, skeletal abnormalities, impaired reproduct-

ive performance, ataxia, and defects in lipid and

carbohydrate metabolism.

0022 The effects of manganese deficiency on bone

development have been studied extensively. In most

species, manganese deficiency can result in shortened

and thickened limbs, curvature of the spine, and

swollen and enlarged joints. The basic biochemical

defect underlying the development of these bone

defects is a reduction in the activities of glycosyl-

transferases; these enzymes are necessary for the

synthesis of the chondroitin sulfate side-chains of

proteoglycan molecules. In addition, manganese

deficiency in adult rats can result in an inhibition of

both osteoblast and osteoclast activity. The implica-

tions of this observation for human bone disease need

to be ascertained.

0023 One of the most striking effects of manganese

deficiency occurs during pregnancy. When pregnant

animals are deficient in manganese, their offspring

exhibit a congenital, irreversible ataxia characterized

by incoordination, lack of equilibrium, and retraction

of the head. This condition is the result of impaired

development of the otoliths, the calcified structures

in the inner ear responsible for normal body right-

ing reflexes. The block in otolith development is

secondary to depressed proteoglycan synthesis due

to the low activity of manganese-requiring glycosyl-

transferases.

0024Defects in carbohydrate metabolism, in addition to

those described above, have been shown in manga-

nese-deficient rats and guinea-pigs. In the guinea-pig,

perinatal manganese deficiency results in pancreatic

pathology, with animals exhibiting aplasia or marked

hypoplasia of all cellular components. Manganese-

deficient guinea-pigs and rats given a glucose chal-

lenge respond with a diabetic-type glucose tolerance

curve. In addition to its effect on pancreatic tissue

integrity, manganese deficiency can directly impair

pancreatic insulin synthesis and secretion. The mech-

anism(s) underlying the effects of manganese on

pancreatic insulin metabolism have not been fully

delineated; however, it is known that insulin mRNA

levels are reduced in the deficient animal. In addition,

insulin sensitivity in adipose tissue is reduced in man-

ganese-deficient rats, a phenomenon that may be re-

lated to fewer insulin receptors per adipose cell in the

deficient animals. Finally, the effect of manganese

deficiency on insulin production may also be due to

the destruction of pancreatic b-cells. It is worth

noting that constitutive pancreatic MnSOD activity

is lower than in most tissues; this, coupled with the

observation that most diabetogenic agents function

via the production of free radicals with subsequent

tissue damage, suggests that an additional mechanism

underlying pancreatic dysfunction in the manganese-

deficient animals may be free-radical mediated. (See

Carbohydrates: Digestion, Absorption, and Metabol-

ism; Glucose: Glucose Tolerance and the Glycemic

(Glycaemic) Index.)

0025Although the majority of studies concerning the

influence of manganese deficiency on carbohydrate

metabolism have been conducted with experimental

animals, there is one report in the literature of an

insulin-resistant diabetic patient who responded to

oral doses of manganese with decreasing blood glu-

cose concentrations. While this is an intriguing case

report, others have reported a lack of an effect of oral

manganese supplements in diabetic subjects, and low

blood manganese concentrations have not been found

to be a characteristic of diabetics.

0026Abnormal lipid metabolism is also characteristic

of manganese deficiency; a lipotrophic effect of

manganese has been suggested. Severely manganese-

deficient animals can be characterized by high liver

fat, hypocholesterolemia and low high-density lipo-

protein concentrations. As stated above, tissue lipid

peroxidation rates can be increased in manganese-

deficient animals, possibly as a result of low tissue

MnSOD activity. (See Fatty Acids: Metabolism;

Lipoproteins.)

MANGANESE 3689

0027 There is considerable debate as to the extent to

which manganese deficiency affects humans under

free living conditions. It has been shown that manga-

nese deficiency can be induced in humans under

highly controlled experimental conditions. In this

study, manganese deficiency was induced in adult

male subjects by feeding a manganese-deficient diet

for 39 days. The subjects developed a temporary

dermatitis, and increased serum calcium and phos-

phorus concentrations and increased alkaline phos-

phatase activity, suggestive of bone resorption.

0028 During the last decade, several diseases have

been reported to be characterized in part, by low

blood manganese concentrations. These diseases

include epilepsy, mseleni disease, maple syrup urine

disease and phenylketonuria, Down’s syndrome,

osteoporosis, and Perthes disease. The finding of

low blood manganese levels in subsets of individuals

with the above diseases is significant since blood

manganese levels can reflect soft-tissue manganese

concentrations. The reports of low blood manganese

concentrations in individuals with epilepsy are

particularly intriguing, given the observations that

manganese-deficient animals can show an increased

susceptibility to drug and electroshock-induced

seizures and a genetic model for epilepsy in rats

(the GEPR rat) is characterized by low blood

manganese concentrations. Given that Mn

2þ

is impli-

cated in activation of glutamine synthetase, a Mn

2þ

specific brain ATPase, production of cyclic-AMP,

altered synaptosomal uptake of noradrenalin and

serotonin, glutamate, GABA and choline metabolism

and biosynthesis of acetylcholine receptors, it is

evident that a deficiency of manganese may con-

tribute to the pathology of epilepsy at multiple

points.

0029 Although it is evident from the above that the role

of altered manganese metabolism in several disease

states needs to be clarified, evidence of widespread

manganese deficiency in human populations is still

lacking. Typically, manganese intakes are within the

USA estimated safe and adequate daily dietary

intakes, which are as follows: 0.3–1.0 mg d

1

for

infants, 1.0–3.0 mg d

1

for children, and 2.0–5.0

mg d

1

for older children, adolescents, and adults.

Manganese Toxicity

0030 In domestic animals, the major reported lesion as-

sociated with chronic manganese toxicity is iron

deficiency, resulting from an inhibitory effect of

manganese on iron absorption. Additional signs of

manganese toxicity in domestic animals can include

depressed growth, depressed appetite, and altered

brain function.

0031In humans, manganese toxicity represents a serious

health hazard, resulting in severe pathologies of the

central nervous system. In its most severe form, the

toxicosis is manifested by a permanent crippling

neurological disorder of the extrapyramidal system,

which is similar to Parkinson’s disease. In its milder

form, the toxicity is expressed by hyperirritability,

violent acts, hallucinations, disturbances of libido,

and incoordination. The above symptoms, once es-

tablished, tend to persist even after the manganese

body burden returns to normal. While the majority

of reported cases of manganese toxicity occur in indi-

viduals exposed to high concentrations of airborne

manganese (> 5 mg m

3

), subtle signs of manganese

toxicity including delayed reaction time, impaired

motor coordination, and impaired memory have

been observed in workers exposed to airborne man-

ganese concentrations lower than 1 mg m

3

. Manga-

nese toxicity has been reported in an individual who

consumed high amounts of manganese supplements

for several years and in individuals who have con-

sumed water containing high levels of manganese.

There has been concern recently that the risk for

manganese toxicity may be increasing in some areas

because of the use of methylcyclopentadenyl manga-

nese tricarbonyl in gasoline as an antiknock agent;

however, this is an issue of active debate.

0032In additional to neural damage, reproductive and

immune system dysfunction, nephritis, testicular dam-

age, pancreatitis, lung disease, and hepatic damage

can occur with manganese toxicity, though the fre-

quency of these disorders is unknown. Similarly to the

cases in humans, chronic manganese toxicity in

rhesus monkeys is characterized by muscular weak-

ness, rigidity of the lower limbs, and neuron damage

in the substantia nigra. Neural toxicity is a consistent

finding in rats exposed to chronic manganese toxicity.

The mechanisms underlying the toxicity of manga-

nese have not been agreed upon but probably involve

both endocrinological dysfunction and excessive

tissue oxidative damage.

0033To date, cases of manganese toxicity in humans

have only been reported for adults; however, infants

may be at a high risk for manganese toxicity owing to

a high absorptive capacity for the element and/or an

immature excretory pathway for it. If manganese is

taken up by extrahepatic tissues via the manganese–

transferrin complex, the developing brain may be

particularly sensitive to manganese toxicity owing to

the high number of transferrin receptors elaborated

by neuronal cells during development, coupled with

the putative need by neural cells for transferrin for

their differentiation and proliferation. Studies aimed

at evaluating the relative sensitivity of the developing

brain to manganese toxicity are needed.

3690 MANGANESE

Biomarkers for Manganese Status

0034 At present, reliable biomarkers for the assessment of

manganese status have not been identified. Whole-

blood manganese concentrations have been reported

to be reflective of soft-tissue manganese levels in rats;

however, it is not known whether a similar relation-

ship holds for humans. Plasma manganese concen-

trations have been shown to decrease in individuals

fed manganese-deficient diets, and to be slightly

higher than normal in individuals consuming manga-

nese supplements. Lymphocyte MnSOD activity has

been reported to be increased in individuals who

consume manganese supplements; however, its value

as a biomarker for manganese status may be compli-

cated owing to the number of cytokines and disease

states, which may also increase its expression.

See also: Bioavailability of Nutrients; Calcium:

Physiology; Carbohydrates: Digestion, Absorption, and

Metabolism; Cereals: Dietary Importance; Dietary Fiber:

Effects of Fiber on Absorption; Fatty Acids: Metabolism;

Glucose: Glucose Tolerance and the Glycemic

(Glycaemic) Index; Iron: Physiology; Lipoproteins; Meat:

Nutritional Value; Phytic Acid: Nutritional Impact; Tea:

Chemistry