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*
Division of Neonatology, Department of Pediatrics, Georgetown University Medical Center Washington, D.C. 20007,
Plant, Soil and Nutrition Laboratory, U.S. Department of Agriculture ARS, Ithaca, NY 14853-2901 and
**
Department of Chemistry, University of Massachusetts, Amherst, MA 01003-4510
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONKinetic studiesOpportunities provided by new...Kinetic studies of the...Areas for research using...REFERENCES |
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KEY WORDS: • humans • rats • zinc mathematical modeling • compartmental model
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONKinetic studiesOpportunities provided by new...Kinetic studies of the...Areas for research using...REFERENCES |
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). The power of this approach
is that it enables differences, in terms of sites and rates of
metabolism, to be determined in conditions that have been modified by
diet, environment, genetics or disease. We first outline a kinetic study and then review in vivo studies in humans and animals. Next, new analytical techniques for increasing the information obtained from kinetic studies are discussed. Finally, some areas that can now be researched using this approach are presented.
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Kinetic studies |
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TOPABSTRACTINTRODUCTIONKinetic studiesOpportunities provided by new...Kinetic studies of the...Areas for research using...REFERENCES |
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), but they have some disadvantages. For example, the
amount of a stable isotope administered to obtain sufficient enrichment
may be such that the system being studied may be perturbed by the mass
of tracer administered. Also, some stable isotopes are very expensive. A second component of a kinetic study is measurement of the tracer in the system (e.g., various tissues) over time. This is necessary to determine the shape of the curves associated with each tissue. The appearance of tracer in a tissue indicates how rapidly it is being taken up, whereas the disappearance indicates how rapidly it is being lost and whether there are multiple pools in the tissue. Obtaining data at a single time point after tracer administration provides no information on the kinetics of a system.
The third component relates to analysis of the kinetic data. To
interpret kinetic curves in a quantitative manner requires computer
modeling, in which the model consists of one or more mathematical
equations. There are a number of approaches to modeling, and the
approach chosen depends on the purpose for the study and the volume of
data (i.e., length of study, number of sites sampled, and so on).
Mechanistic models, such as compartmental models, are useful for
describing the behavior of a system in terms of pools and transfer
pathways. Compartmental models may be large if the purpose is to
explore the underlying physiology or pathophysiology. If the purpose of
the study is to determine a specific characteristic, e.g., the turnover
based on whole body data, a simpler model with fewer parameters may be
sufficient. Both types of models are useful, but it is important to
understand the limitations of each. Complex models have heuristic value
in indicating areas in which data are lacking and in making predictions
for further experimental testing even though not all parameters may be
identifiable from a particular experiment. Simple models tend to lump
together various processes. One example is the use of fecal monitoring,
where absorption is determined as the difference between orally
administered dose and the dose recovered in feces. As described by
Janghorbani et al. (1980)
and simulated by
Wastney and Henkin (1989)
, accurate calculation of
absorption using this model is affected by transit times through the
intestine. Transit times affect how quickly unabsorbed tracer is
excreted and how much absorbed tracer is resecreted. Although simpler
models may be well determined (i.e., all parameters of the model can be
determined with statistical confidence), the values are reliable only
if the model is a correct representation of the physiological system.
Previously computing and software limitations favored the use of
smaller models, but these limitations no longer need apply.
Kinetic studies in humans.
Some kinetic studies (Babcock et al. 1982
,
Fairweather-Tait et al. 1993
, Foster et al. 1979
, Henkin et al. 1984
, Lowe et al. 1993
, 1997
, Miller et al. 1998
,
Scott and Turnlund 1994
, Wastney et al. 1986
, 1991
, 1996
) involving zinc
that include the three criteria described above (use of tracers,
collection of data over time and analysis of the data with the use of a
model) are listed in Table 1
. Earlier studies used radioactive isotopes, and this allowed data
collection external to the body and for the studies to be performed for
a longer duration. After the development of techniques for their
analysis in biological tissues, stable isotopes have been used in many
studies conducted during the past decade. Fewer sampling sites are
available with stable isotopes, and some investigators have used models
with lumped compartments to analyze the data. It also is appropriate to
apply the more extensive models developed from radioisotope data to the
studies with stable isotopes.
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, Lowe et al. 1997
), whereas longer-term studies (weeks to months) have
been used in addition to study the tissue pools that turnover more
slowly (Babcock et al. 1982
, Foster et al. 1979
, Miller et al. 1998
, Wastney et al. 1986
). These studies have shown that there are multiple pools
of zinc that turnover within minutes to years. The faster pools are
located in plasma, liver and red blood cells, and the slower pools are
located in muscle and bone.
Zinc kinetics have been determined in healthy subjects consuming either
normal or relatively high amounts of zinc. By comparing the changes in
the kinetics attributable to zinc intake, it was found that processes
at five sites, including absorption and excretion, are regulated to
maintain tissue levels during high zinc intake (Wastney et al. 1986
). By comparing kinetic data in healthy adults age 20–84
y, it was shown that although a few values changed while subjects
consumed their normal dietary intake of zinc, there were significant
changes with age at four sites of zinc regulation when the subjects
consumed supplemental zinc (Wastney et al. 1992
). The
results may indicate either a reduced need for zinc or a reduced
ability to regulate the amount of zinc retained with aging.
Rates of zinc absorption and retention have been ascertained in preterm
infants (Wastney et al. 1996
). Because the infants were
growing during the study, it was necessary to model both tracer and
tracee (total zinc). In addition, it was necessary to model clinical
interventions, such as blood transfusions, because the administration
of adult blood cells provided a significant source of zinc to the
infants. The results from a population of infants who were healthy and
growing at expected rates (Wastney et al. 1999
) can be
used to evaluate zinc metabolism and requirements in infants who are
sick or growing slowly.
By comparing zinc kinetics in subjects with normal, high or low copper
intake, Scott and Turnlund (1994)
investigated sites of
interaction between copper and zinc and the degree of interaction at
each site. They reported that zinc absorption was lower on high copper
intake (28 versus 34%, respectively). This is the only report of which
we are aware that used zinc kinetics to study element–element
interactions.
Kinetic studies in animals.
Animal studies allow a greater understanding of kinetics because more
tissues can be sampled and environmental and genetic factors can be
controlled. Table 2
shows some studies of zinc kinetics in animals (Dunn and Cousins 1989
, House and Wastney 1997
, Lowe et al. 1991
, Lowe et al. 1995
, Popov and Besel 1977
, Serfass et al. 1996
). In one study with
rats (House and Wastney 1997
), zinc kinetics were
measured in 15 tissues, and the data were analyzed using modeling
techniques. In addition to providing baseline values for healthy
animals, the study (House and Wastney 1997
) revealed the
existence of slow and fast pools of zinc in muscle and bone and showed
that three pools observed in humans, which turned over in 4 h,
1.3 d and 50 d, were consistent with kinetics in kidney,
spleen and testes, respectively, in rats.
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). Results showed that animals fed the deficient diet
compensated by increasing fractional absorption; however, liver zinc
levels remained lower in the zinc-deficient piglets than in the
control animals. The latter suggested that although growth rates were
equivalent over the study period, subsequent growth and overall health
would probably be compromised in the zinc-deficient group.
Long-term studies (>6 mo) in humans fed mildly zinc-deficient
diets showed that fractional absorption was increased but the increase
was not sustained (Lee et al. 1993
).
Dunn and Cousins (Dunn 1991
, Dunn and Cousins 1989
) studied the effect of metallothionein induction on zinc
kinetics in vivo in rats. They found that induction caused increased
redistribution of zinc among body tissues; there was a fourfold
increase in zinc uptake by liver metallothionein and a 85% decrease in
release of zinc from hepatic metallothionein. The kinetics provided an
understanding of the mechanisms involved in zinc redistribution between
tissues and between pools within liver after metallothionein induction.
Kinetic studies in animals will provide information on the overexpression of and deletion of genes coding for specific proteins involved in zinc transport and metabolism. By comparing kinetics in wild types with those in mutants, the role of specific proteins can be determined in vivo. Studies are in progress to describe the role of metallothionein on zinc kinetics in knockout mice (House, W. A. & Wastney, M. E., unpublished data).
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Opportunities provided by new analytical techniques |
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TOPABSTRACTINTRODUCTIONKinetic studiesOpportunities provided by new...Kinetic studies of the...Areas for research using...REFERENCES |
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, 1996
,
1998a
). New developments will allow more detailed
kinetics to be described in at least three ways (Barnes 1998b
). First, increased levels of stable isotope detection
will allow smaller doses to be administered, reducing the risk of the
dose perturbing the system and reducing cost. Second, methods are being
developed to measure isotope enrichment in various zinc-binding
species (e.g., metalloproteins and metalloenzymes) within blood and
other tissues (Lu and Barnes 1996
, Lu et al. 1995
). Measurement of the kinetics of zinc bound to different
species may provide insight into the forms of zinc that are the most
active physiologically. Third, multielement studies will be possible in
which the kinetics of several elements will be determined
simultaneously on the same subject. This will allow interactions to be
studied more extensively and sites, as well as the degree of
interaction, to be determined. |
Kinetic studies of the role of zinc in health |
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TOPABSTRACTINTRODUCTIONKinetic studiesOpportunities provided by new...Kinetic studies of the...Areas for research using...REFERENCES |
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). For example, patients with adrenal corticosteroid
insufficiency have increased serum zinc and decreased urine zinc
levels, and kinetic studies showed that zinc uptake by erythrocytes and
liver was low in these patients (Henkin et al. 1984
).
Rates of zinc uptake were restored by steroid treatment, and the
increase in uptake is considered to occur through metallothionein
induction in these tissues.
To understand the roles of zinc in metabolism, kinetic studies are
needed in both healthy and disease states. For example, zinc kinetics
in healthy preterm infants (Wastney et al. 1996
,
1999
) could be used to assess whether zinc metabolism is
perturbed in infants who are growing at suboptimal rates and, if so, at
which sites. By knowing whether zinc absorption, endogenous excretion
or uptake by tissues is perturbed, rather than whether serum levels are
altered, it may be possible to more fully understand the role of zinc
in human health and to devise therapeutic strategies and dietary
recommendations.
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Areas for research using kinetic studies |
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TOPABSTRACTINTRODUCTIONKinetic studiesOpportunities provided by new...Kinetic studies of the...Areas for research using...REFERENCES |
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). Models will be
increasingly used to integrate information from the cellular to the
whole body level (Bassingthwaighte 1995
). They will be
refined to account for changes in metabolism in different physiological
and clinical conditions. Most current models are based on kinetic
studies in the steady state, but they will be increasingly used to
understand the dynamics of zinc metabolism, when zinc levels change
such as after a meal, during dietary perturbations or during growth.
Models can be used to represent the current understanding of a system,
to identify gaps in knowledge and in experimental design to ensure that
necessary and sufficient data are collected to determine parameters of
interest. In the future, models will play a greater role in the design
of studies as well as in the interpretation of data. With respect to nutrition, kinetic studies can be used to determine the sites where zinc interacts with other nutrients, including trace elements, vitamins and macrominerals; to determine the degree of interaction; and to predict how these interactions may alter zinc requirements. With respect to physiology, kinetic studies could address how rates of zinc metabolism and pool sizes change under different physiological and clinical conditions, such as during growth or pregnancy. By comparing kinetics in healthy and various disease states, the roles of zinc in disease may be elucidated through the identification of differences in metabolic processes. From an environmental perspective, it is important to know how zinc interacts with nonessential metals, and this information can be obtained from kinetic studies. Finally, a powerful use of kinetics will be to study and define the role of gene products in vivo by comparing kinetics in the wild type versus conditions in which the genes are overexpressed or missing. In conclusion, although tissue levels provide a snapshot of the zinc status, kinetic studies allow the exploration of mechanisms, such as the pathways of metabolism, rates of movement and sites of homeostasis, that vary with conditions such as diet, genetics and disease.
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FOOTNOTES |
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2 Supported by National Institutes of Health R01-DK53787.
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REFERENCES |
|---|
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TOPABSTRACTINTRODUCTIONKinetic studiesOpportunities provided by new...Kinetic studies of the...Areas for research using...REFERENCES |
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1. Babcock A. K., Henkin R. I., Aamodt R. L., Foster D. M., Berman M. Effects of oral zinc loading on zinc metabolism in humans. II: In vivo kinetics. Metabolism 1982;31:335-347
2. Barnes R. M. Advances in inductively coupled plasma mass spectrometry: human nutrition and toxicology. Anal. Chim. Acta 1993;283:115-130
3. Barnes R. M. Analytical plasma source mass spectrometry in biomedical research. Fresenius J. Anal. Chem. 1996;355:433-441
4. Barnes R. M. Capillary electrophoresis and inductively coupled plasma spectrometry: status report. Fresenius J. Anal. Chem. 1998a;361:246-251
5. Barnes R. M. Plasma source mass spectrometry in experimental nutrition. Adv. Exp. Med. Biol. 1998b;445:379-396[Medline]
6. Bassingthwaighte J. B. Toward modeling the human physionome. Adv. Exp. Med. Biol. 1995;382:331-339[Medline]
7. Dunn M. A. Hormonal induction of metallothionein synthesis: its effect on zinc kinetics in the rat. Klaassen C. D. Suzuki K. T. eds. Metallothionein in Biology and Medicine 1991:283-294 CRC Press Boca Raton, FL.
8.
Dunn M. A., Cousins R. J. Kinetics of zinc metabolism in the rat: effect of dibutyryl cAMP. Am. J. Physiol. 1989;256(Endocrinol. Metab.19.):E420-E430
9. Fairweather-Tait S. J., Jackson M. J., Fox T. E., Wharf S. G., Eagles J., Croghan P. C. The measurement of exchangeable pools of zinc using the stable isotope 70Zn. Br. J. Nutr. 1993;70:221-234[Medline]
10.
Foster D. M., Aamodt R. L., Henkin R. I., Berman M. Zinc metabolism in humans: a kinetic model. Am. J. Physiol. 1979;237:R340-R349
11. Henkin R. I., Foster D. M., Aamodt R. L., Berman M. Zinc metabolism in adrenal cortical insufficiency: effects of carbohydrate-active steroids. Metabolism 1984;33:491-501[Medline]
12.
House W. A., Wastney M. E. Compartmental analysis of zinc kinetics in mature male rats. Am. J Physiol. 1997;273:R1117-R1125
13. Janghorbani M., Ting B. T. G., Young V. R. Accurate analysis of stable isotopes 68Zn, 70Zn, and 58Fe in human feces with neutron activation analysis. Clin. Chim. Acta 1980;108:9-24[Medline]
14. Lee D.-Y., Prasad A. S., Hydrick-Adair C., Brewer G., Johnson P. E. Homeostasis of zinc in marginal human deficiency: role of absorption and endogenous excretion of zinc. J. Lab. Clin. Med. 1993;122:549-556[Medline]
15. Lowe N. M., Bremner I., Jackson M. J. Plasma 65Zn kinetics in the rat. Br. J. Nutr. 1991;65:445-455[Medline]
16. Lowe N. M., Green A., Rhodes J. M., Lombard M., Jalan R., Jackson M. J. Studies of human zinc kinetics using the stable isotope 70Zn. Clin. Sci. 1993;84:113-117[Medline]
17. Lowe N. M., Hall E. J., Anderson R. S., Batt R. M., Jackson M. J. A stable isotope study of zinc kinetics in Irish setters with gluten-sensitive enteropathy. Br. J. Nutr. 1995;74:69-76[Medline]
18.
Lowe N. M., Shames D. M., Woodhouse L. R., Matel J. S., Roehl R., Saccomani M. P., Toffolo G., Cobelli C., King J. C. A compartmental model of zinc metabolism in healthy women using oral and intravenous stable isotope tracers. Am. J. Clin. Nutr. 1997;65:1810-1819
19. Lu Q., Barnes R. M. Evaluation of an ultrasonic nebulizer interface for capillary electrophoresis and inductively coupled plasma mass spectrometry. Microchem. J. 1996;54:129-143
20. Lu Q., Bird S. M., Barnes R. M. Interface for capillary electrophoresis and inductively coupled plasma mass spectrometry. Anal Chem 1995;67:2949-2956
21. Miller L. V., Krebs N. F., Hambidge K. M. Human zinc metabolism: advances in the modeling of stable isotope data. Adv. Exp. Med. Biol. 1998;445:253-269[Medline]
22. Popov B. V., Besel V. S. Mathematical model of zinc metabolism in rat: imitation of zinc deficient and zinc excessive diets. Kirchgessner M. eds. Proceedings of the Trace Element Metabolism in Man and Animals (TEMA3) 1977;Vol. 3 Arbeitskreis Tierernährungsforschung Weihenstephan Freising-Weihenstephan
23.
Reyes J. G. Zinc transport in mammalian cells. Am. J. Physiol. 1996;270(2 pt 1):C401-C410
24.
Scott K. C., Turnlund J. R. A compartmental model of zinc metabolism in adult men used to study effects of three levels of dietary copper. Am. J. Physiol. 1994;267:E165-E173
25. Serfass R. E., Fang Y., Wastney M. E. Zinc kinetics in weaned piglets fed marginal zinc intake: compartmental analysis of stable isotopic data. J. Trace Elem. Exp. Med. 1996;9:73-86
26.
Vallee B. L., Falchuk K. H. The biochemical basis of zinc physiology. Physiol. Rev. 1993;73:79-118
27.
Wastney M. E., Aamodt R. L., Rumble W. F., Henkin R. I. Kinetic analysis of zinc metabolism and its regulation in normal humans. Am. J. Physiol. 1986;251:R398-R408
28.
Wastney M. E., Ahmed S., Henkin R. I. Changes in regulation of zinc metabolism with age. Am. J. Physiol. 1992;263:R1162-R1168
29.
Wastney M. E., Angelus P., Barnes R. M., Siva Subramanian K. N. Zinc kinetics in preterm infants: a compartmental model based on stable isotope data. Am. J. Physiol. 1996;271(Regul. Integ. Comp. Physiol. 40):R1452-R1459
30. Wastney M. E., Angelus P. A., Barnes R. M., Siva Subramanian K. N. Zinc absorption, distribution, excretion, and retention by healthy preterm infants. Pediatr. Res. 1999;45:191-196[Medline]
31.
Wastney M. E., Gokmen I. G., Aamodt R. L., Rumble W. F., Gordon G. E., Henkin R. I. Kinetic analysis of zinc metabolism in humans after simultaneous administration of 65Zn and 70Zn. Am. J. Physiol. 1991;260:R134-R141
32. Wastney M. E., Henkin R. I. Calculation of zinc absorption in humans using tracers by fecal monitoring and a compartmental approach. J. Nutr. 1989;119:1438-1443
33. Wastney M. E., Patterson B. H., Linares O. A., Greif P. C., Boston R. C. Investigating Biological Systems Using Modeling: Strategies and Software 1998 Academic Press New York.
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