Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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family, GATA-1, GAL4, the so-called RING-finger

proteins (Really Interesting New Gene), and p53.

p53 zinc-binding proteins seem to play important

roles in the development/suppression of cancer. p53

seems to be involved in the induction of cell-cycle

arrest upon identification of increased genomic

DNA damage. About 50% of human cancers may

involve a p53 dysfunction.

0025 Zinc and membranes Zinc is a structural compon-

ent of cellular and subcellular membranes. Although

its specific roles are only partially known, a number

of studies have demonstrated alterations when zinc is

reduced in these structures. These include changes in

protein structure and lipid concentration, increased

red cell fragility and abnormal platelet aggregation,

and reduced activities of selected enzymes, such as

Ca-ATPase, 5

nucleotidase and alkaline phosphatase.

0026 Under physiological conditions the major role of

zinc is not to be a membrane stabilizer, as previously

considered, but a permissive factor for cell signaling.

Zn acts by binding to, and maintaining, the tertiary or

quaternary structure of several key proteins involved

in signal transduction. A crucial feature in zinc

deficiency is a defect in calcium channels function,

specifically a reduced calcium uptake as result of an

abnormal sulfhydril redox state in the membrane

channel protein.

Regulatory

0027 Zinc is involved in regulatory functions. One remark-

able example is the regulation of the protein metal-

lothionein (MT). MT is a small metal-binding protein

characterized by a high cysteine content and a high

affinity for heavy metals. There are four isoforms of

MT. The functional significance of MTs is not well

understood. It is a rather nonspecific metal-buffering

ligand to retain or deliver metal ions. Among the

proposed roles for MT are: metal donation to target

apometallothioneins such as zinc fingers proteins and

enzymes, metal detoxification, and protection against

oxidative damage. It can also act as a short-term

storage reservoir for the metals.

0028 The transcription of MT genes can be activated,

among others, by a number of metals, including zinc,

copper, and cadmium. Zn is the most important in

eukaryotic cells. The regulation of MT gene expres-

sion by zinc and other metals occurs via the inter-

action of the metals with multiple cis-acting DNA

elements called metal response elements located in

the MT gene promoters.

0029 Another regulatory function of zinc is that related

to the modulation of the gene-directed cell death

process, or apoptosis. A number of studies have

demonstrated the importance of maintaining an

intracellular pool of zinc atoms to regulate this pro-

cess. In vitro studies have shown that apoptosis is

induced when cells are cultured in a zinc-free medium

or when zinc is depleted by membrane-permeant zinc

chelators. The exact mechanism by which Zn ions

intervenes in preventing or reducing apoptosis is not

completely understood. Zinc may interact with one

or more participants of the apoptosis process. Thus,

initial studies have proposed that zinc inhibits the

activity of the Ca–Mg-dependent endonuclease,

whereas others have proposed that zinc might block

the mechanism by which the inactive procaspase-3 is

activated. Zinc is a selective inhibitor of caspase 6,

which promotes activation of caspase-3. It has also

been proposed that zinc may participate through its

antioxidant roles.

0030A series of recent reports have documented the

participation of zinc in a variety of signal-related

functions. Thus, b-2 adrenergic receptors are allo-

sterically modulated by zinc. Zinc has been shown

to increase the excitability of dopaminergic neurons

in rat substantia nigra, to modulate signals from red-

and short wavelength-sensitive cones to horizontal

cells in carp retina, and to induce the stimulation of

the c-Jun N-terminal kinase signaling pathway

through phosphoinositide 3-kinase. Some observa-

tions in cultured cells have suggested the existence

of a zinc-sensing receptor that triggers the release of

intracellular Ca

2þ

and regulates ion transport.

Zinc Determination

0031Compared with other essential or toxic trace elem-

ents, such as selenium or arsenic, zinc does not pre-

sent any major problems for its determination in a

wide variety of matrices, and consequently, a large

number of methods are used for its quantification. A

detailed discussion of the basis, advantages, and limi-

tations of each methodology is beyond the scope of

this chapter, but there is abundant literature else-

where on specific issues relating to zinc.

Principal Methods to Determine Zinc in Biological

and Environmental Samples

0032The methods used to determine zinc are based on

several physical, chemical, and nuclear characteristics

of the atoms, including zinc. Some of the methods

used to determine zinc are listed in Table 4.

0033Atomic absorption and atomic emission spectrom-

etry are based on the property of the atoms to absorb

or emit light energy during energy transition from

ground states to excited states or during decay. By

far the most commonly used method to determine

zinc is atomic absorption spectrometry (AAS). For

zinc, the analysis is usually conducted using a

6270 ZINC/Properties and Determination

wavelength of 213.9 nm. This method provides accur-

ate and precise results, and the cost of the equipment

and maintenance are low compared with most of the

other techniques. The detection limit in its flame

mode is about 100 mgl

1

(or 100 p.p.b.). This detec-

tion limit is greatly improved, more than 200 times,

when used with the graphite furnace. The significant

improvement in sensitivity is also accompanied by a

higher degree of interferences, mainly matrix effects.

Similarly, the sensitivity of atomic emission spectrom-

etry is improved when inductively coupled plasma is

used. Unlike flame atomic absorption spectrometry

(FAAS) or graphite furnace atomic absorption spec-

trometry,inductively coupled plasma-atomic emission

spectrometry provides the capacity for performing

multielemental analyses. Potentiometric methods,

such as differential pulse anodic stripping voltam-

metry have shown analytical performances com-

parable with FAAS in simple matrices. The main

advantage of potentiometric methods is the sim-

plicity of the equipment and lower costs. It has

been suggested as a candidate for routine clinical

chemistry.

0034 The group of nuclear analytical methods suitable

for zinc determination includes a number of methods,

such as: energy-dispersive X-ray fluorescence, total

reflection X-ray fluorescence, proton-induced X-ray

emission (PIXE), photon activation analysis, and

instrumental neutron activation analysis (INAA),

among others. These methods have detection limits

in the range of p.p.b. to p.p.t. Some of them are based

on the excitation of characteristic X-rays in a sample

by electromagnetic radiation from an X-ray tube

or radioactive source (X-ray fluorescence methods) or

by accelerated charged particles (PIXE). Photon-

activated analysis is based on photon emission after

irradiation. INAA is a multielemental method that

has been widely used for zinc and other trace element

analysis. It is based on the measurement of the g

radiation produced after irradiation. For zinc, the

reaction is

Zn (n, g)

Zn. Gamma radiation from

the long-lived nuclide

Zn is usually measured

15 days after irradiation.

0035Inductively coupled plasma mass spectrometry

(ICP-MS) has shown remarkable advances in sensitiv-

ity and reliability for mineral analysis. The regular

equipment is an ICP-quadrupole mass spectrometer,

which has a detection limit in the range of p.p.t. with

concomitant high precision and accuracy. This is a

versatile technique that can be coupled to chromatog-

raphy systems for other applications such as high-

performance liquid chromatography–ICP-MS. New

versions of high-performance ICP-MS include ICP

magnetic sector-MS and ICP ion trap-MS. These are

intended to reach detection limits in the low p.p.t.–

p.p.q. range. ICP-MS can determine not only the total

element concentration but also its individual stable

isotopes.

0036The use of stable isotopes has proven to be a

powerful tool in the field of zinc nutrition and zinc

metabolism. Because they do not emit radiation, they

can be safely used as tracers in any age/physiological

condition group. This requires techniques with the

capacity for performing highly accurate and precise

determination of isotope ratios. Among the methods

suitable for stable isotope determinations are:

neutron activation analysis, electron ionization-mass

spectrometry, gas chromatography-mass spectrom-

etry, fast atom bombardment-mass spectrometry,

thermal ionization mass spectrometry (TIMS), and

ICP-MS. Of these, TIMS and ICP-MS are recognized

as the techniques with the best results in terms of

accuracy, precision, and sensitivity.

0037Regardless of the method used to determine zinc,

an appropriate quality assessment of the procedures

should be conducted, considering both precision and

bias evaluation. The former is conducted through

repetitive measurements and internal test samples,

and the latter is accomplished through a series of

actions such as the use of different operators or equip-

ments, use of reference materials, participation in

intercomparison rounds, external audits, etc.

0038The determination of zinc in biological samples

can serve several purposes. One of the most com-

monly used applications has been the assessment

of zinc status. Thus, zinc has been determined in:

plasma, serum, hair, skin, semen, sweat, saliva,

urine, neutrophils, lymphocytes, platelets, erythro-

cytes, and erythrocyte membranes. Although the de-

terminations of zinc in these fluids or tissues have

been conducted appropriately from an analytical

point of view, they have shown limitations as indica-

tors of zinc nutriture. These limitations also extend

to other methods such as the activity of several

zinc enzymes, including alkaline phosphatase

(EC 3.1.3.1), a-d-mannosidase (EC 3.2.1.24),

tbl0004 Table 4 Methods to determine zinc in biological and

environmental samples

Flame atomic absorption spectrometry

Graphite furnace atomic absorption spectrometry

Atomic emission spectrometry

Inductively coupled plasma-atomic emission spectrometry

Differential pulse anodic stripping voltammetry

Energy-dispersive X-ray fluorescence

Total reflection X-ray fluorescence

Proton-induced X-ray emission

Photon activation analysis

Instrumental neutron activation analysis

Inductively coupled plasma mass spectrometry

ZINC/Properties and Determination 6271

nucleotidase (EC 3.1.3.5), angiotensin-1-convert-

ing enzyme (EC 3.4.15.1), and several functional

tests. (See Nutritional Assessment: Biochemical Tests

for Vitamins and Minerals.)

See also: Nutritional Assessment: Biochemical Tests for

Vitamins and Minerals; Zinc: Physiology; Deficiency

Further Reading

Berthon G (ed.) (1995) Handbook of Metal–Ligand Inter-

actions in Biological Fluids, vol. 1. New York: Marcel

Dekker.

Davis SR and Cousins RJ (2000) Metallothionein expres-

sion in animals: a physiological perspective on function.

Journal of Nutrition 130: 1085–1088.

de Goeij JJM (1994) Nuclear analytical methods in the

life sciences. Biological Trace Element Research 43–45:

9–17.

Green A, Parker M, Conte D and Sarkar B (1998) Zinc

finger proteins: a bridge between transition metals and

gene regulation. Journal of Trace Elements in Experi-

mental Medicine 11: 103–118.

Locatelli C and Torsi G (2001) Heavy metal determination

in aquatic species for food purposes. Annali di Chimica

91: 65–72.

McCall KA, Huang Ch and Fierke CA (2000) Function and

mechanism of zinc metalloenzymes. Journal of Nutrition

130: 1437S–1446S.

Mellon FA and Sandstrom B (1996) Stable Isotopes in

Human Nutrition. London: Academic Press.

Mills CF (ed.) (1989) Zinc in Human Biology. London:

Springer-Verlag.

O’Dell BL (2000) Role of zinc in plasma membrane func-

tion. Journal of Nutrition 130: 1432S–1436S.

Yergey AL (1996) Analytical instruments for stable isotopic

tracers in mineral metabolism. Journal of Nutrition 126:

355S–361S.

Physiology

N W Solomons, CeSSIAM, Guatemala City, Guatemala

Background

0001 It was first established in 1869 by Raulin that zinc

was essential for the growth of bread mold. In the

twentieth century, it was discovered that zinc was

essential for the growth of rats and to prevent the

parakeratitis dermatological condition of swine. The

essentiality of zinc, and its requirements, has been

established in species from the protozoa, Euglena

gracilis, to the steelhead trout. Most recently, the

critical role that nutrition plays in the nutrition of

the retrovirus of AIDS has been revealed. This article

considers three topics: the normal metabolism of zinc

by the body; aberrations of its metabolism; the

physiological and biochemical functions of zinc for

the organism. Emphasis will be placed on zinc in

human nutrition.

Normal Metabolism of Zinc

Absorption of Zinc

0002Mechanisms of normal absorption Zinc is not

absorbed in the esophagus or stomach but can be

taken up along all parts of the small intestine (duode-

num, jejunum, and ileum) with varying efficiencies

and, to some extent, in the large bowel. The form of

zinc in the diet, soluble in beverages or bound in food

matrices, may determine the part of the alimentary

tract in which the zinc is absorbed. In healthy

humans, the fractional absorption of isotopically

labeled oral zinc ranges from 40 to 70% from aque-

ous solutions and 2 to 40% in the presence of various

foods and meals.

0003The cellular mechanisms and kinetics of zinc ab-

sorption have been studied extensively. It is likely that

zinc, freed from food, is complexed to some small

molecules as it approaches the brush border. Uptake

across the mucosal membrane can be by a simple

diffusion (nonsaturable) mechanism of low permeabi-

lity and dependent upon the concentration gradient

between lumen and blood, taking a paracellular

pathway after membrane transport or by a carrier-

mediated and energy-dependent (saturable) mechan-

ism, which is most important at low intraluminal

concentrations.

0004Once within the cell, an element of zinc has a

multitude of possible designations. It can become

part of the zinc nutrition of the enterocyte, itself;

it can remain in the cell, eventually being bound

to metallothionein (MT), a 6000–7000-Da peptide,

with 61 amino acid residues, and then lost back into

the lumen of the intestine when the cell is desquam-

ated; or it can pass on to the serosal surface of the cell,

possibly bound to intracellular ligands or binding

proteins to be released into the body. The level of

preexisting MT in the cell has been thought to regu-

late the amount of zinc available for exit into the

bloodstream, but microvesicles may participate in

the transport of the zinc that is eventually taken up

by the circulation. The final exit step of zinc into the

body may be energy-dependent, coupled to basal

membrane adenosine triphosphate.

0005Zinc absorption appears to be homeostatically

regulated, in so far as uptake is reduced in sufficiency

6272 ZINC/Physiology

or excess, whereas in deficiency, the uptake is en-

hanced. In zinc-depleted subjects, more than 90% of

a highly available dose can be absorbed. The amount

that passes through the enterocyte by diffusion is

related to the mucosal–serosal gradient and is unre-

lated to the zinc status of the host. It is the carrier-

mediated active absorption that is responsive to

underlying zinc nutrition. In animal experiments

and human experience, zinc absorption from the

diet has been shown to increase during both preg-

nancy and lactation.

0006 The more zinc there is available to the intestine in a

meal, the lower is its fractional absorption. However,

the amount of zinc that reenters the intestinal lumen

is now recognized to be a dynamic function of the

quantity of the mineral absorbed from the diet. (See

Lactation: Physiology; Human Milk: Composition

and Nutritional Value.)

0007 Bioavailability of zinc from the diet Bioavailability

strictly refers to both the uptake and metabolic util-

ization of a nutrient. Since different valence states or

chemical species are not an issue with zinc, the bio-

logical availability of zinc relates exclusively to the

efficiency of its absorption. (See Bioavailability of

Nutrients.)

0008 In theory, zinc must be either in soluble form or

bound to soluble, absorbable species to be absorbed

by the intestine. The efficiency of mastication and

gastric and pancreatic protease digestion of food de-

termines the extraction of zinc from its food matrices.

Once liberated and dissolved, the zinc ion needs to

remain in solution and proceed in its transit through

or around the enterocytes.

0009 Substances that influence intestinal permeability to

zinc are also mediators of bioavailability. A series of

dietary substances influence the bioavailability of

zinc, either by chelating or binding zinc or by com-

petitively inhibiting its absorption. Two common

components of whole-grain cereals – phytic acid and

dietary fibre – are the most important substances that

interfere with zinc absorption. Polyphenolic sub-

stances (tannins) in tea and coffee and oxalic acid of

green leafy herbs are also inhibitors. Calcium and

dietary nonheme iron are two inorganic elements

that interfere with zinc uptake by direct competition.

(See Dietary Fiber: Effects of Fiber on Absorption;

Phytic Acid: Nutritional Impact.)

0010 Alternatively, a series of compounds have been

suggested as enhancers or promoters of zinc absorp-

tion, including amino acids, sugars, picolinic acid,

citric acid, and prostaglandins. Only the first two

classes of compound are likely to be of physiological

significance. Red wine has been shown to enhance

zinc balance under metabolic conditions. Ascorbic

acid and lactose have a neutral influence on zinc

bioavailability.

0011It should be remembered that bioavailability refers

to a fractional efficiency of uptake, and the total

amount of zinc ingested is a codeterminant of how

much net nutrient will be absorbed. If the zinc intake

is high in a diet of poor zinc bioavailability, the

amount absorbed may still be sufficient to support

true nutritional requirements.

0012Enteropancreatic circulation With each meal, a

large volume of bile, pancreatic juice, and salivary,

gastric, and intestinal secretions are secreted into the

intestinal lumen, with pancreatic juice being the

richest in the metal. Within the lumen, the endogen-

ous zinc forms a common pool with that from oral

intake. Some of the pancreatic zinc is not recovered

and passes into the stools, but a substantial part is

reabsorbed and becomes part of internal metabolism

once more. This constitutes an enteropancreatic cir-

culation for endogenous zinc. By virtue of this ‘double

jeopardy’ of zinc to dietary inhibitors, the body can

be more rapidly depleted of this nutrient than of most

others.

0013Net daily zinc metabolic balance In growing indi-

viduals, more zinc should be taken in than excreted

on average on any given day. Adults with a normal

total body content of zinc should be in essentially zero

balance, with the amount absorbed equal to the

amount lost by all routes (see below). In pregnancy

and lactation, the products of conception and the

daily secretion of milk represent additional depots

for newly absorbed zinc. In 1973, an expert commit-

tee of the WHO first used a factorial approach to

estimate the amount of zinc that must be absorbed

daily to account for deposition for growth and losses

from the body in infants, children, and adolescents,

and to account for losses in adults. This amount of

zinc is often referred to as the ‘true zinc requirement,’

to distinguish it from the daily dietary intake require-

ment, and the daily dietary allowance. Estimations

of the amount of dietary zinc to be absorbed daily

have been refined by subsequent consultancies, the

most recent being from the World Health Organiza-

tion and the International Atomic Energy Agency in

1996 and from the US Food and Nutrition Board in

their Dietary Reference Intakes process in 2001. For

infants aged 6–12 months, it is 0.8 mg; for children

aged 6–10 years, 1.1 mg; for men over 18 years,

1.4 mg; and for women over 18 years, 1.0 mg. During

pregnancy, absorption daily from zinc in the diet

should be 1.5 mg, rising to 1.8 mg during the first

6 months of lactation, and declining to 1.4 mg during

the duration of the period of breast-feeding. Of

ZINC/Physiology 6273

course, the amount of zinc reabsorbed from the en-

dogenous sources of the mineral that enters intestinal

lumen as part of pancreatic, biliary, and intestinal

secretions with meals is at least equivalent to the

dietary requirement. So, a rough calculation of the

daily net absorptive demand across the intestine

would involve a doubling of the aforementioned

age- and physiology-specific values. (See Dietary

Requirements of Adults.)

Distribution and Transport of Zinc

0014 Distribution of zinc The total body content of zinc

in normal individuals has been measured by isotopic

dilution studies and ranges from 1.5 to 2.5 g. It is

higher in men than in women and decreases with

increasing age in adults. At the tissue level, the con-

tent of zinc is heterogeneous, ranging from 20 to

200 mgg

1

in most tissues, and up to 600–800 mg

1

in pancreas, gonads, and retina. Within the cell,

zinc is ubiquitous but compartmentalized, being

found in nuclear, mitochondrial, and cytosolic

fractions.

0015 The two major depots for zinc in the body are

skeletal muscle and the skeleton, which contains, re-

spectively, 57 and 29% of the zinc in an individual.

Skin and liver share an additional 10%. The percent-

age of the total body content of zinc in the 7-l volume

of peripheral circulation is less than 0.1%.

0016 The uptake of newly absorbed zinc is greatest in the

liver. Structural tissues, such as bone and skin, and

functional tissues, such as kidney, thymus, pancreas,

and gonads, have high rates of uptake, which implies

high rates of intracellular turnover.

0017 Transport of zinc Zinc that passes through and

around the enteral cell, from the intestinal lumen,

enters the capillary circulation of the gut and returns

by the mesenteric and portal circulation to the liver.

Some of the zinc is taken up by hepatic cells, and the

remainder passes into the systemic circulation.

0018 Since zinc would be filtered and lost by the kidney

were it not bound to large, nonfilterable molecules

or to reabsorbed species, it circulates in bound states

in the systemic circulation. Forty per cent of zinc is a

covalently linked component of a

-macroglobulin,

and most of the remainder is loosely bound to

serum albumin. A small fraction is chelated to

serum free amino acids or small peptides. About 3–

5 mg of newly absorbed zinc and additional quan-

tities moving from one site to another pass through

the circulation daily; the flux of the transport pool

is rapid. Hormones (glucocorticoids, glucagon cat-

echolamines) and monokines (interleukin-1, tumor

necrosis factor) modify zinc uptake and turnover in

peripheral tissues. Whether or not a peripheral cell

zinc receptor exists for the capture of the nutrient

from the systemic bloodstream has not been deter-

mined.

0019In reproductive biology, two additional aspects of

zinc transport – transplacental and mammary gland

transport – are important in normal metabolism. Zinc

can move bidirectionally from the maternal circula-

tion to the fetus, and from the fetus to the mother,

but the net flux is toward the fetus. The flux is rapid,

and the size of the transfer is proportional to the mass

of the fetus, increasing with advancing gestation.

Some 75% of the zinc in amniotic fluid is bound to

albumin. The exact mechanism for transfer of zinc

from plasma to mammary gland, and within the

gland into the breast milk, is poorly understood.

The concentration of zinc decreases progressively

with duration of lactation. A multinational study of

seven countries, conducted by the International

Atomic Energy Agency, showed that zinc concentra-

tions in breast milk vary from nation to nation, and

within countries from rural to urban dwellers. How-

ever, in experimental studies, high oral doses of zinc

did not modify the zinc content of healthy mothers.

Retention and Excretion of Zinc

0020Zinc storage and retention Despite the relatively

large amount of zinc in the body, and its ubiquitous

distribution, most is either in active functions in

metabolism or in nonretrievable deposits in bone,

muscle, and integument. There is a consensus that

if any metabolic storage pool of zinc exists to act as

a reserve against nutritional compromise, it is small

in relation to the total body content of the mineral.

It is now postulated that the mobile exchangeable

zinc pool constitutes about 10% of the total body

zinc, i.e., is 150–250 mg. Thus, a cumulative deficit

of 100–200 mg, i.e., the obligatory losses of 20–40

days, could be critical.

0021In tissues with active uptake and turnover of zinc,

such as liver, kidney, pancreas, and gut, the metal-

binding protein MT is prominent, and its synthesis

is regulated and responsive to zinc availability. MT

expresses its high affinity for divalent cations and is

related to the 20 sulfur-containing cysteine residues.

It is believed to constitute a cytosolic storage pool or

buffer to regulate concentrations of free ions within

the cytoplasm. It has a rapid turnover of 20 h and is

subject to regulation or influence by a number of

hormones and pathological conditions.

0022Zinc excretion A number of routes are available for

zinc excretion from the body. In the zinc-adequate

state, the excretion is proportional to the total body

burden of the nutrient. Some pathways for zinc

excretion are not regulated. Among these are those

6274 ZINC/Physiology

via the integumentary tissues, i.e., the growing out of

hair, the desquamation of skin, and sweating.

0023 The major route for excretion of the zinc of the

active metabolic pool is into the fecal stream from

pancreatic and intestinal secretions. Low zinc status

produces conservation of zinc, whereas zinc excess

leads to enhanced fecal excretion. Adults chronically

consuming 10–15 mg of dietary zinc excrete about

500 mg of zinc in the urine daily. With severe zinc

restriction, the renal excretion in 24 h is reduced to

200 mg. When zinc is perfused parenterally or con-

sumed orally in pharmacological amounts, a mani-

fold increase in renal excretion is observed.

Pathophysiological Metabolism of Zinc

0024 Several conditions can produce a pathophysiological

metabolism of zinc. Its malabsorption is produced

in short-gut or pancreatic insufficiency. Diarrheal

disease, protein-losing (exudative) enteropathy, and

enterocutaneous fistulas produce a wasting of en-

dogenous zinc into the stools. Excessive renal losses

are seen in primary renal disease, in certain endocri-

nopathies such as diabetes mellitus, with infection

and stress, and with severe exercise.

0025 Infection and stress induce a cascade of hormonal

responses including the secretion of glucocorticoid

and catecholamine hormones and the peptides from

circulating monocytes and fixed macrophages (cyto-

kines), which produce an internal redistribution of

zinc with redirection of the mineral to the liver and

the bone marrow. A primary effect of the hormones

and cytokines may be to induce the synthesis of MT,

which captures and holds zinc in the cells. A teleo-

logical explanation of this filtering of zinc from blood

to liver and bone marrow would be to facilitate the

hepatic synthesis of acute-phase protein and the pro-

liferation of new lymphocytes or neutrophils.

Physiological, Metabolic, and

Biochemical Functions of Zinc

Physiology at the System Level

0026 Below is a comprehensive listing of the physiological

and metabolic functions of mammalian organisms,

including humans, that are dependent on zinc. The

inference of their dependence is based primarily on

zinc-restriction experiments in laboratory animals

and livestock, along with some zinc-deprivation

experiments in humans, in which the performance is

altered with decreasing zinc status.

0027 growth of cells;

0028 replication of cells;

0029 antioxidant (antifree radical) protection;

0030regulation of neurotransmission;

0031insulin and leptin metabolism;

0032sexual maturation;

0033spermatogenesis;

0034oogenesis;

0035cellular apoptosis;

0036dark adaptation or scotopic vision;

0037cellular immunity;

0038humoral immunity;

0039appetite regulation;

0040taste acuity;

0041olfactory acuity;

0042cognitive function.

Biochemistry at the Cellular and Molecular Level

0043Zinc is a unique element among the traditional metals

in so far as it exists exclusively in the divalent oxida-

tion state and has no redox potential. Its coordination

chemistry is alternatively tetrahedral (four ligands) or

trigonal bipyramidal (five ligands) geometry, coordin-

ated by the negative charges of a sulfur of cysteine, a

nitrogen of histidine, or an oxygen from aspartate

and glutamate in various combinations. Within the

organized complexes, the protein at the center exerts

an intense positive charge. Zinc in proteins can par-

ticipate directly in catalytic reactions or maintain

stability and structure conformation of proteins.

0044Zinc metalloenzymes A zinc metalloenzyme is an

enzyme that has a specific requirement for zinc as a

cofactor or as an integral, coordinated firmly com-

plexed moiety within the structure of the protein. In

the latter circumstances, the zinc ion(s) can partici-

pate at the active site of the enzyme in its catalytic

activity in either the 4- or 5-coordination configur-

ations in association with a molecule of water. The

transformation of water by the dense charge and

acid–base equilibrium provides the energy for the

catalytic properties. Alternatively, complexed zinc

can serve a role in stabilizing the conformation of

the protein. A selected number of the estimated 300

enzymes in nature that have been confirmed as zinc

metalloenzymes are listed below:

0045aldolase (fructose 1, 6-biphosphatase);

0046alcohol dehydrogenase;

0047alkaline phosphatase;

0048carbonic anhydrase;

0049carboxypeptidase A;

0050carboxypeptidase B;

0051collagenase;

0052d-aminolaevulinate dehydratase;

0053deoxynucleotidyl transferase;

0054DNA polymerase;

0055enkephalinase;

ZINC/Physiology 6275

.0056 glutamic acid dehydrogenase;

0057 lactic dehydrogenase;

0058 malic acid dehydrogenase;

0059 pyruvate carboxylase;

0060 nucleoside phosphorylase;

0061 reverse transcriptase;

0062 DNA polymerase I;

0063 RNA polymerases I, II, and III;

0064 thermolysin;

0065 zinc–copper superoxide dismutase.

Zinc metalloenzymes are not restricted to mamma-

lian enzymes: some examples are found in plants,

bacteria, and viruses. Some of the pathogenesis of

zinc deficiency can be attributed to defects in the

reactions catalyzed by zinc metalloenzymes. For

example, the impaired dark adaptation and night

blindness of zinc deficiency have been attributed to

a defective functioning of the alcohol dehydrogenase

(retinol dehydrogenase), found in the retina, that is

responsible for the conversion of retinol to retinalde-

hyde for the regeneration of the visual pigment, rhod-

opsin, in the rods of the retina. (See Coenzymes.)

0066 Other putative cellular and molecular roles of

zinc The other generic manner in which zinc, pos-

sibly in a freely exchangeable, ionic form within

the cell, is in the stabilization of membranes, of

membrane–protein associations, and of macromol-

ecular structures. The association of protein kinase

C with cell membranes, for example, depends on zinc.

0067 Zinc has long been known to stabilize polyribo-

somes, and this is one of the putative roles of the

nutrient in protein synthesis. More recently, a role

for zinc, tightly complexed to amino acids in chains

of peptides within the chromatin proteins of the

nucleus of the cell, has been shown for expression of

genetic information. A series of ‘zinc finger’ proteins

have been characterized. The name derives from the

rigid projection of a loop of protein (a finger), stabil-

ized by the zinc in tetrahedral coordination with four

amino acids; the most common motif is one coordin-

ated with two cysteine and two histidine residues.

Over 2000 different domains of these zinc finger

proteins for regulating the expression of specific

genes along the chromosomes, allowing a determined

amount of the genetic code to be translated to its

complementary messenger RNA, have been identified

in the last decade. Functions of enzymes that do not

contain zinc themselves may be impaired in zinc defi-

ciency because of a defect in a zinc finger protein that

governs its translation in the nuclear reserves of

genetic information.

0068 A specific form of transcriptional regulation is

known as the metal regulating element, which is

involved in the regulation of MT synthesis presum-

ably in response to the cellular levels of zinc that exist.

Hence, the amount of zinc entering the cell influences

an MT transcription factor associated with this MRE

in the chromosome coding for MT and accounts for

the up- or downregulation.

0069Two levels of zinc’s participation in genetic expres-

sion, i.e., in zinc finger transcription regulators and in

polyribosome, may also help to support the theory,

proposed by Mills, that increased protein degradation

is a generic consequence of zinc deficiency, one that

explains the defects in growth and the rapidity of the

onset of manifestations after restriction of dietary

zinc.

0070Tissue cells are constantly dividing, but the net cell

mass of an organ remains constant. Apoptosis is the

process of genetically programmed death of cells by

which certain cells within the tissue ‘commit suicide’

to maintain the balance of mass and structure. Each

cell has this potential in a series of ‘procapase’ prote-

ase proenzymes that can become activated to produce

a cascade effect leading to nuclear involution, cyto-

solic dissolution, and loss of attachment. Zinc is

among the dietary constituents involved in this pro-

cess. A decrease in intracellular zinc concentration

precedes the physiological and anatomical cellular

changes of apoptosis.

0071Finally, the molecular basis of zinc’s role in immune

protection has not been elucidated. Its roles in cell

proliferation and thymic function are basic but

combined with regulation of cytokine production,

modulation of apoptosis, and a function of induced

metallothionein as a scavenger of harmful free

radicals in the cell cytoplasm.

See also: Bioavailability of Nutrients; Coenzymes;

Dietary Fiber: Effects of Fiber on Absorption; Dietary

Requirements of Adults; Immunology of Food;

Lactation: Human Milk: Composition and Nutritional

Value; Physiology; Phytic Acid: Nutritional Impact

Further Reading

Davis JS and Cousins RJ (2000) Metallothionein expression

in animals: a physiological perspective on function.

Journal of Nutrition 130: 1085–1088.

Dibley MJ (2001) Zinc. In: Bowman BA and Russell RM

(eds) Present Knowledge in Nutrition, 8th edn,

pp. 329–343. Washington, DC: ILSI Press.

Institute of Medicine, Food and Nutrition Board (2001)

Dietary Reference Intakes for Vitamin A, Vitamin K,

Arsenic, Boron, Chromium, Copper, Iodine, Iron, Man-

ganese, Molybdenum, Nickel, Silicon, Vanadium, and

Zinc. Washington, DC: National Academy Press.

Solomons NW (2001) Dietary sources of zinc and factors

affecting its bioavailability. Food and Nutrition Bulletin

22: 138–154.

6276 ZINC/Physiology

Solomons NW and Ruz M (1998) Trace element require-

ments in humans: An update. Journal of Trace Elements

in Experimental Medicine 11(supplement): 177–195.

World Health Organization/International Atomic Energy

Agency (1996) Trace Elements in Human Nutrition

and Health. Geneva: WHO.

Deficiency

N W Solomons, CeSSIAM, Guatemala City, Guatemala

Background

0001 Zinc is an essential nutrient for all living species.

Human zinc deficiency was first described in patients

as a secondary consequence of alcoholic cirrhosis in

1956. In 1961, human zinc deficiency was first de-

scribed on a dietary basis in rural, Iranian children.

Since then, clinical zinc deficiency has been described

in all age groups from breast-fed infants to the very

elderly. For both the clinical nutrition of hospitalized

patients and the public health at the community level,

human zinc deficiency has emerged as a relevant con-

cern over the past three decades.

Mechanisms for the Pathogenesis of Zinc

Deficiency

0002 Only a very small ‘exchangeable zinc pool,’ sufficient

for a few days’ nutrition, exists in human body, and

the major deposits of the metal in bone or muscle

cannot be readily mobilized for nutritional purposes.

Zinc in excess of short-term metabolic needs is either

excluded from absorption or excreted by the kidneys

or via the alimentary tract. The human organism lives

with a perpetually marginal zinc nutriture by evolu-

tionary design and is dependent upon regular dietary

replenishment.

0003 Certain extrinsic conditions and intrinsic situations

can place an individual at increased risk of zinc deple-

tion. Victor Herbert developed a conceptual frame-

work for understanding the genesis of deficiencies of

any nutrient based on six mechanisms that operate

alone, or in combination, to contribute to the

development of deficiency; these include: decreased

intake, decreased absorption, increased destruction,

increased excretion, decreased utilization, and in-

creased requirements. With the exception of destruc-

tion, which is not relevant to inorganic nutrients, this

scheme provides a focus for understanding the ways

in which human zinc deficiency can occur.

0004With respect to zinc, primary deficiencies arise

when the supply to the body, either by an oral/enteral

(dietary) route or by parenteral nutrition, is insuffi-

cient to match losses and/or meet demands for

growth. Selection of a zinc-poor diet, be it for cul-

tural, socioeconomic or eating-disorder motives, can

produce deficiency. When a patient is dependent on

intravenous nutrition, improper formulation of the

nutrient fluids can precipitate a primary deficiency.

Impaired absorption of zinc results from digestive

difficulties that impede its release from foods, inter-

ference with its mobility or solubility that inhibit its

absorption, or intestinal membrane pathologies that

impair its uptake. Increased zinc losses from the body

can occur as a result of a hemorrhagia, superficial

losses, excessive diuresis, or gastrointestinal tract

wastage into stool. Decreased utilization can occur

in inflammation, infection, and metabolic disorders.

Thermal burns, catch-up growth, multiple pregnan-

cies (twinning, triplets), lactation, and rampant

malignancies are conditions that place additional

demands on the supply of zinc. These factors can

operate alone or in various combinations. In the

case of an inflammatory bowel disease such as severe

Crohn’s enteritis, one might see the combination of:

(1) reduced intake owing to anorexia; (2) impaired

absorption owing to mucosal damage; (3) increased

losses through bleeding and protein-losing enteropa-

thy; and (4) impaired utilization owing to activation

of the acute-phase response. Increased requirements

for zinc might even occur in this disease if an adoles-

cent patient develops a remission leading to rapid

compensatory growth and sexual development after

a period of growth arrest. (See Bioavailability of

Nutrients.)

0005Once the body pool of zinc has contracted beyond

a critical level, however, the exact molecular basis of

the pathogenesis of zinc deficiency is poorly under-

stood. Michael Golden has classified the deficiency of

zinc as a type II nutritional deficiency, similar to defi-

ciencies of the intracellular nutrients nitrogen, phos-

phorus, magnesium, and potassium, in which there is

conservation of tissue concentrations at the expense

of growth and development. This is especially true of

zinc deficiency in experimental animals, in which

restriction of the nutrient produces marked anorexia,

immediate cessation of growth and reproductive cap-

acity, and even weight loss; combined with regulated

conservation of nutrient, it allows the ratio of body

zinc content to body mass to remain relatively

constant. Animals will not readily eat a zinc-deficient

ration that is producing a deficiency state. Only with

force-feeding will a diet of low zinc density produce

tissue desaturation. In humans, however, social and

cultural factors intercede to overcome whatever

ZINC/Deficiency 6277

anorexia might result from consumption of a zinc-

poor diet or one that has a poor zinc bioavailability;

thus, people – as opposed to animals – will consume

generous amounts of energy and protein while on

zinc-deficient diets. An opposing combination of con-

servation and desaturation of tissue zinc can therefore

occur in humans. The fact that a certain degree of

conservation of tissue zinc is maintained under con-

ditions of zinc-poor diets does not eliminate the pos-

sibility of the intracellular and molecular roles of the

nutrient being disrupted and altered by the responses

to zinc deprivation.

0006 How the deficiency manifestations, described

below, are related to zinc deficiency at the tissue and

cellular level is still poorly understood. Between 60

(conservative estimate) and 300 (generous estimate)

enzymes, are believed to be zinc metalloenzymes or

enzymes dependent on zinc as a cofactor in their

catalytic activity. Specifically, the disruption of cell

proliferation that leads to growth failure and to im-

pairment of function of cells in the gut and bone

marrow that are rapidly turning over can be attrib-

uted to the defects in enzymes responsible for DNA

regeneration and RNA production. Furthermore,

over 2000 nuclear transcription factors that employ

zinc to regulate their protein configuration during

gene activation (zinc finger proteins) have been iden-

tified in the past decade. Recently, in vitro experi-

ments have confirmed that decreasing cellular zinc

restricts the expression of a zinc-finger transcription

factor for regulation of interleukin-2 in lymphocytes.

Zinc deficiency promotes protein degradation and

enhances protein turnover; this would explain both

the rapid response to zinc deficiency by growing

animals and the limitation of total growth. (See

Coenzymes.)

0007 The loss of stabilization of intracellular structures

by zinc in a freely exchangeable intracellular form

also accounts for some of the molecular defects in

zinc deficiency. Zinc is thought to stabilize mem-

branes, to stabilize ribosomes, and to contribute to

associations between membranes and functional pro-

teins. Soluble zinc plays a role in signaling among

cells and between compartments within cells.

Manifestations of Zinc Deficiency

Clinical Signs and Symptoms

0008 Deficiency in laboratory animals and livestock We

have understood human zinc deficiency better using

the basis in its observation and study in laboratory

rodents, as well as poultry, swine, ruminants, felines,

canines, and subhuman primates. The dietary regi-

mens have various formats, including ad libitum

feeding of a zinc-poor diet with pair-feeding of

control animals as well as force-feeding of an energy-

adequate, zinc-depleted ration. Clinical manifest-

ations documented in zinc restricted animals have

included dermatitis and hair loss, depressed immune

functions, altered reproductive performance, terato-

genesis, and skeletal abnormalities.

0009Deficiency in human adults Although the anorectic

response does not dominate in humans with either

primary, experimental or secondary zinc deficiency,

substantial homology exists between the clinical

manifestations in animals and those in humans. The

manifestations of zinc deficiency in humans have

been catalogued from observations of iatrogenic defi-

ciency, genetic predisposition (acrodermatitis entero-

pathica), patients with secondary deficiency, endemic

deficiency situations, and experimental depletion in

volunteers. Recently, there has been a trend to use the

response of populations suspected of endemic zinc

deficiency to define functional manifestations of defi-

ciency. As a rule, as the severity of zinc deprivation

increases, there are a wider array and a greater inten-

sity of clinical manifestations. In chronic deficiency,

the zinc deficiency manifestations have a gradual

onset, whereas in acute deficiency, signs and symp-

toms appear rapidly.

0010The manifestations of human zinc deficiency

include the following: behavioral alterations and

central nervous system change (anorexia, depression,

psychosis, hypogeusia, hyposmia, night blindness,

seizure disorder, impaired cognitive performance);

integumentary changes (bullous, pustular lesions;

keratotic lesions; rough skin; loss of scalp, facial and

body hair; impaired wound healing); gastrointestinal

manifestations (diarrhea, impaired nutrient digestion

and absorption); impaired growth and development

(linear growth retardation; weight loss); altered re-

productive biology (oligospermia; hypogonadism and

reduced potency; fetal teratogenesis); and impaired

immunity (recurrent infections; reduced delayed

cutaneous hypersensitivity). Situations such as acute

deficiency induced during total parenteral nutrition,

or the congenital zinc malabsorption syndrome,

acrodermatitis enteropathica, can bring out the most

severe extremes, with manifestations from all systems.

In a mild deficiency, anorexia, dry rough skin and

oligospermia may be the only manifestations.

0011Deficiency in children and adolescents All of the

signs and symptoms discussed above for adults, with

the exception of those related to reproductive func-

tion, can be manifested in children and adolescents.

However, the imperative of growth and development

add additional dimensions to clinical manifestations.

6278 ZINC/Deficiency

Slow growth leading to growth retardation or even

periods of growth arrest are seen in pediatric zinc

deficiency. The juvenile deficiency also delays devel-

opment of puberty and secondary sexual characteris-

tics in both boys and girls. A neonatal seizure disorder

has been ascribed to zinc deficiency in preterm

infants, a manifestation apparently unique to this

specific age-group. (See Adolescents; Children: Nutri-

tional Problems; Nutritional Requirements; Infants:

Nutritional Requirements.)

Physiological and Metabolic

Consequences

0012 Certain physiological and metabolic consequences

of human zinc deficiency do not manifest with clinical

signs and symptoms, but are detectable in the

laboratory. The physiological alterations of zinc

deficiency (information gathered from animal experi-

ments or experimental restrictions in humans), in-

cluding structural changes in microstructures,

hematological abnormalities, metabolic and endo-

crinological alterations, immune defense defects, ner-

vous system problems, changes in the homeostatic

regulation of zinc supply, and assorted miscellaneous

changes, are summarized below:

0013 impaired cell replication;

0014 impaired collagen synthesis and cross-linking;

0015 disorganized tubulin synthesis;

0016 dysplasia of buccal and esophageal mucosa;

0017 dense inclusion bodies in Paneth cells of the

intestine;

0018 changes in pancreatic exocrine secretion;

0019 impaired tocopherol absorption;

0020 impaired platelet aggregation and prolonged bleed-

ing time;

0021 increased amino acid oxidation;

0022 reduced leptin gene expression and leptin secretion;

0023 elevated plasma ammonium levels;

0024 impaired rhodopsin regeneration in retina;

0025 synthesis of retinol-binding protein and transport

of retinol;

0026 impaired insulin secretion;

0027 impaired glucose tolerance;

0028 elevated cholesterol;

0029 deranged essential fatty acid and prostaglandin

metabolism;

0030 decreased gonadal hormone production;

0031 increased lipid peroxidation;

0032 impaired cellular immunity;

0033 decreased CD4þ : CD8þ T-cell ratio;

0034 decreased CD73þ/CD11b T-cell ratio in the CD8þ

subset;

0035 thymic hypoplasia and atrophy;

0036decreased production of thymulin;

0037structural changes in the brain;

0038decreased seizure thresholds;

0039changes in neurotransmitter storage and metabol-

ism;

0040decreased peripheral nerve conduction time;

0041alteration of taste bud morphology;

0042decreased metallothionein synthesis in liver and

intestine;

0043enhanced absorption of dietary zinc;

0044increased retention of zinc; decreased urinary and

fecal loss;

0045decreased growth of tumors;

0046impaired thermal regulation.

Assessment of Human Zinc Nutriture

0047The assessment of human zinc nutriture is compli-

cated and confounded by issues related both to zinc

biology and to analytical chemistry. In theory, the

approach to define the status of an individual for

any nutrient is to measure the total body pool and/

or its availability to the sites of activity. In Golden’s

concept of a type II nutritional deficiency, the overall

amount of zinc in the body or its concentrations in the

tissues will not be severely altered; rather, adaptations

such as growth arrest and retarded development will

occur at an early stage of sensing zinc restriction, and

tissue concentrations will be relatively conserved.

Tests that Assess the Total Body Pool and Various

Component Pools

0048The only conceivable direct approach to estimating

total-body zinc content is in a postmortem chemical

examination or by in vivo neutron activation analy-

sis. Neither is practical in the context of patients or

populations. One can estimate total-body zinc by

isotopic techniques. Radiozinc (

Zn) and several

stable isotopes serve in this connection. However,

such is the nature of zinc biology that it makes it

inappropriate to speak of standing zinc ‘stores’ or

‘reserves.’ For this reason, biopsies of various tissues

such as bone and muscle would provide a less than

useful index of zinc that is available for metabolic

purposes.

0049Rather than ask how much total zinc is in the body,

we must search for indicators of the metabolically

active or nutritionally relevant zinc. Using multiple

isotopes and complex mathematics, the size of vari-

ous component pools, including the ‘exchangeable

zinc pool’ can be estimated to provide a reliable esti-

mation of individual ‘nutriture.’ More commonly,

less expensive indirect measures are used, with the

circulating concentration of zinc (in plasma or serum)

being the most common, followed by whole-blood

ZINC/Deficiency 6279