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Iron Absorption in Mice: Two Concurrent Mechanisms, Study Guides, Projects, Research of Pediatrics

AIB InternationalPediatrics

The kinetics of iron absorption in mice using single doses labeled with Fe59. The study reveals that iron absorption is mediated by at least two different mechanisms: an enzymatic or carrier-mediated process and a first-order process. The amount of iron absorbed is influenced by the state of body iron stores, with absorption being inhibited by an increase and enhanced by a decrease.

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Journal
of
Clinical
Investigation
Vol.
41,
No.
2,
1962
ON
THE
KINETICS
OF
IRON
ABSORPTION
IN
MICE*
BY
DAVID
GITLIN
§
AND
ANDRE
CRUCHAUD
t
(From
the
Department
of
Pediatrics,
Harvard
Medical
School,
and
the
Children's
Hospital
Medical
Center,
Boston,
Mass.)
(Submitted
for
publication
June
9,
1961;
accepted
October
12,
1961)
In
individuals
with
similar
body
stores
of
iron,
the
amount
of
iron
absorbed
from
a
single
oral
dose
is
not
proportional
to
the
amount
of
iron
administered.
Although
a
greater
amount
of
iron
is
absorbed
as
the
size
of
the
oral
dose
in-
creases,
the
percentage
or
fraction
of
the
dose
that
is
absorbed
actually
decreases
(1-3).
In
addition,
the
amount
of
iron
absorbed
from
a
given
dose
is
dependent
upon,
among
other
things,
the
iron
stores
of
the
body
(1,
4-6).
Thus,
an
individual
with
deficient
iron
stores,
due
solely
to
deficient
iron
intake,
tends
to
absorb
more
iron
from
a
given
dose
than
someone
with
normal
iron
stores,
while
the
normal
person
tends
to
absorb
more
iron
from
the
same
dose
than
the
individual
with
excessive
iron
stores
accumulated
through
a
large
iron
intake.
Although
it
has
been
established
that
the
size
of
the
dose
and
the
state
of
the
iron
stores
of
the
body
both
influence
the
absorption
of
iron,
the
biological
processes
through
which
the
absorption
of
iron
is
regulated
are
unknown.
It
has
been
suggested
that
iron
absorption
may
be
controlled
either
by:
1)
the
degree
of
saturation
of
an
intra-
cellular
iron
carrier,
e.g.,
ferritin
(7)
;
2)
the
degree
of
saturation
of
a
plasma
carrier
of
iron,
or
transferrin
(8);
3)
cellular
enzymatic
mecha-
nisms
(9,
10);
4)
the
tension
of
oxygen
at
the
cellular
level
(11);
or
5)
the
degree
of
erythro-
poiesis
(1).
None
of
these
hypotheses
has
gained
wide
acceptance.
It
has
recently
been
observed
that
the
absorp-
tion
of
copper
is
related
to
the
amount
of
copper
ingested
in
a
manner
qualitatively
similar
to
the
relationship
between
dose
and
amount
absorbed
for
iron
(12).
An
analysis
of
this
relation
in-
dicated
that
copper
absorption
is
mediated
through
*
Supported
by
Grants
A-251
and
2G-338
from
the
Na-
tional
Institutes
of
Health,
U.
S.
Public
Health
Service.
§
This
work
was
done
during
tenure
of
an
Established
Investigatorship
of
the
American
Heart
Association.
t
Fellow
of
L'Academie
Suisse
des
Sciences
medicales.
two
mechanisms:
1)
a
first-order
process
wherein
the
amount
of
copper
absorbed
is
proportional
to
the
amount
of
copper
ingested,
and
2)
an
enzy-
matic
or
carrier
process
which
becomes
saturated
or
less
efficient
as
the
amount
of
copper
ingested
increases.
When
the
intake
of
copper
is
low,
the
carrier
process
is
the
more
important
in
terms
of
amounts
of
copper
absorbed,
while
at
high
in-
takes
of
copper
the
first-order
process
is
the
more
significant
(12).
In
the
study
reported
here,
the
processes
regulating
the
absorption
of
iron
were
investigated
in
a
similar
fashion:
an
attempt
was
made
to
analyze
the
relationship
between
the
size
of
the
dose
of
iron
and
the
amount
of
iron
ab-
sorbed
and
to
determine
the
influence
of
the
state
of
the
body
stores
of
iron
upon
this
relationship.
MATERIALS
AND
METHODS
Swiss
albino
female
mice
of
the
Webster
strain
were
selected
for
study.
The
mice
were
6
to
7
weeks
of
age
at
the
onset
of
the
investigation
and
had
an
average
weight
of
14
g.
They
were
kept
on
zinc
screens
in
plastic
cages,
the
feces
and
urine
falling
through
the
screen
to
the
bottom
of
the
cage
where
the
urine
was
absorbed
by
paper
toweling.
The
mice
were
divided
into
6
groups.
Group
N
and
group
N.,
mice
with
normal
iron
stores,
were
maintained
on
a
Purina
laboratory
chow
diet
which
contained
ap-
proximately
335
mg
of
iron
per
kg
of
diet.
Although
each
mouse
consumed
approximately
1
to
1.5
mg
of
dietary
iron,
the
amount
of
this
iron
that
could
be
uti-
lized
by
the
animals
was
unknown.
Group
Fe
and
group
Fe,,
mice
with
excessive
iron
stores,
were
kept
on
the
same
diet
as
the
group
N
mice,
but
each
mouse
was
inj
ected
with
5
mg
of
iron
in
an
iron-dextran
complex
(Imferon)
subcutaneously
once
a
day
for
5
days
for
a
total
of
25
mg
of
iron.
The
sig-
nificance
of
the
size
of
this
dose
may
be
judged
from
the
observation
that
the
injection
of
10
mg
of
iron
as
iron-
dextran
into
mice
was
almost
uniformly
fatal
within
6
hours.
Group
D.,
mice
with
deficient
iron
intake,
were
main-
tained
for
6
weeks
on
a
synthetic
diet
of
purified
casein,
corn
oil,
glucose,
vitamins,
and
essential
salts
with
the
exception
of
iron.
The
diet
provided
less
than
2
Ag
of
iron
per
mouse
per
day,
but
the
mice
gained
weight
in
344
pf3
pf4
pf5

Partial preview of the text

Download Iron Absorption in Mice: Two Concurrent Mechanisms and more Study Guides, Projects, Research Pediatrics in PDF only on Docsity!

Journal of Clinical Investigation Vol. 41, No. 2, 1962

ON THE KINETICS OF IRON ABSORPTION IN MICE*

BY DAVID GITLIN § AND ANDRE CRUCHAUD (^) t (From the Department of Pediatrics, Harvard Medical School, and the Children's Hospital

Medical Center, Boston, Mass.)

(Submitted for publication June 9, 1961; accepted October 12, 1961)

In individuals with similar body stores of iron, the amount of iron absorbed from a single oral dose is not proportional to the amount of iron administered. Although a greater amount of iron is absorbed as the size of the oral dose in- creases, the percentage or fraction of the dose that is absorbed actually decreases (1-3). In addition, the amount of iron absorbed from a given dose is dependent upon, among other things, the iron stores of the body (1, 4-6). Thus, an individual with deficient iron stores, due solely^ to^ deficient iron intake, tends to absorb more iron from a

given dose than someone with normal iron stores,

while the normal person tends to absorb more

iron from the same dose than the individual with

excessive iron stores accumulated through a large iron intake.

Although it has been established that the size

of the dose and the state of the iron stores of the

body both influence the absorption of iron, the

biological processes through which the absorption

of iron is regulated are unknown. It has been

suggested that iron absorption may be controlled

either by: 1) the degree of saturation of an intra-

cellular iron carrier, e.g., ferritin (7) ; 2) the

degree of saturation of a plasma carrier of iron,

or transferrin (8); 3) cellular enzymatic mecha-

nisms (9, 10); 4) the tension of oxygen at the

cellular level (11); or 5) the degree of erythro-

poiesis (1). None of these hypotheses has gained

wide acceptance.

It has recently been observed that the absorp-

tion of copper is related to the amount of copper

ingested in a manner qualitatively similar to the

relationship between dose and amount absorbed

for iron (12). An analysis of this relation in-

dicated that copper absorption is mediated through

  • (^) Supported by Grants A-251 and 2G-338 from the Na- tional Institutes of Health, U. S. Public Health Service. § This^ work^ was^ done^ during^ tenure^ of^ an^ Established Investigatorship of the American Heart Association. t Fellow^ of^ L'Academie^ Suisse^ des^ Sciences^ medicales.

two mechanisms: 1) a first-order process wherein the amount of copper absorbed is proportional to the amount of copper ingested, and 2) an enzy- matic or carrier process which becomes saturated

or less efficient as the amount of copper ingested

increases. When the intake of^ copper^ is^ low,^ the

carrier process is the more important in terms

of amounts of copper absorbed, while at high in-

takes of copper the first-order process is the more

significant (12). In the study reported here, the

processes regulating the absorption of iron were investigated in a similar fashion: an attempt was

made to analyze the relationship between the size

of the dose of iron and the amount of iron ab- sorbed and to determine the^ influence^ of^ the^ state of the body stores of iron upon this relationship.

MATERIALS AND METHODS Swiss albino female mice of the Webster strain were selected for study. The mice were 6 to 7 weeks of age at the onset of^ the^ investigation and^ had^ an^ average weight of 14 g. They were kept on^ zinc^ screens^ in plastic cages, the feces and urine falling through the screen to the bottom of the cage where the urine was absorbed by paper toweling. The mice were^ divided^ into^6 groups. Group N^ and group N., mice with normal^ iron^ stores, were^ maintained on a Purina laboratory chow diet which contained ap- proximately 335 mg of iron per kg of diet. Although each mouse consumed^ approximately 1 to^ 1.5^ mg of dietary iron, the amount of^ this^ iron^ that could^ be uti- lized by the animals was unknown. Group Fe^ and^ group^ Fe,,^ mice^ with^ excessive^ iron stores, were^ kept on^ the^ same^ diet^ as^ the^ group N^ mice, but each mouse^ was^ inj ected^ with^5 mg of^ iron^ in^ an iron-dextran complex (Imferon) subcutaneously once a day for 5 days for^ a^ total^ of^25 mg of^ iron.^ The^ sig- nificance of the size of this^ dose^ may be^ judged from^ the observation that the injection of^10 mg of^ iron^ as^ iron- dextran into mice was almost uniformly fatal^ within^6 hours. Group (^) D., mice with deficient iron intake, were main- tained for 6 weeks on a synthetic diet of purified casein, corn (^) oil, glucose, vitamins, and essential salts with the exception of^ iron.^ The^ diet^ provided less^ than^2 Ag of iron (^) per mouse (^) per day, but the mice gained weight in 344

KINETICS OF IRON ABSORPTION IN MICE

much (^) the same way as the mice on the regular chow diet. Group (D and Fe)., mice on synthetic diet and normal iron intake, were kept for 6 weeks on the same diet as the group D. mice but with the addition of 350 mg of

iron as FeSO, per kg of diet. This provided about 1 to

1.5 mg of iron per mouse per day. Varying amounts^ of^ FeSO4 labeled with Fe5' were then given to the mice directly into the stomach through a polyethylene catheter. The mice of group N and group Fe received the dose of labeled iron without prior fasting, but the (^) remaining groups, designated by the subscript s, received the labeled iron after a period of 24 hours dur- ing which food was withheld. The animals of group Fe and group Fe. were given the labeled iron 36 hours after the last injection of iron-dextran. A given (^) dose of labeled iron was administered to each of four mice of each group. The amount of iron in each dose given to all groups except group N. and group (D and (^) Fe). was approximately: 0.11 or 0.65, 5, 10, 25, 50, 100, 500, and 1,000 (^) Ag; groups of four (^) mice in (^) group N also (^) received 2,000 and 3,000 (^) 1Ag of labeled iron. The mice of group N. received only doses of 100, 500, and

1,000 /Ag and those of group (D and Fe). received doses

of 50, 100, 500, and 1,000 (^) ,ug. It (^) should be noted that the

LD,, for iron given as a solution of FeSO, into the

stomach in these mice was 3,000 ug, which corresponded to an (^) LD. of about 200 mg of iron per kg of body weight. Each dose of labeled iron was 0.2 ml in volume and con- tained 0.7 to 1.0 (^) ,uc of Fe5'. (^) The amount of iron actually received by each (^) animal was (^) determined from the amount of radioactivity present in the animal soon after the dose was given and from the specific activity of the labeled iron given. Beginning about 2 hours after the (^) dose, the animals (^) were allowed access to (^) the regular chow diet. The (^) specificity of (^) the influence of body stores of iron upon iron absorption was examined by studying copper absorption in two other groups: (^) group Ncu, normal (^) mice, maintained on the chow (^) diet, and group Fec., iron-loaded mice, also^ chow-fed but which received in addition 25 mg of iron subcutaneously, as did group Fe. Varying amounts of copper acetate labeled with 0.5 (^) /Ac of Cu" were then placed directly into the stomach (^) through a polyethylene catheter in order to (^) compare the absorp- tion of (^) copper in these (^) two groups. Three mice were used for (^) each dose in (^) each group and the doses used were 1.2, 12, 27, 37, and (^112) /Ag of copper. Each mouse was assayed for radioactivity by counting the whole mouse in a well (^) measuring 1.63 inches in di- ameter and 2.63 inches in (^) depth in a 3 X 3 inch NaI crystal scintillator. When assayed for Fe", the mouse was (^) counted within 10 minutes after administration of the dose, 3 and 6 hours later, at daily intervals for 4 to 5 days, and then on alternate days. When Cu" was as- sayed, the mice were counted within 5 minutes after ad- ministration of the dose, 3, 6, 9, and 12 hours later, and then at 12-hour intervals for a total of (^3) days. The amount of iron or copper remaining in an animal at a given time from a given dose was determined from the

z

a 0 00 4 IL 10.

0

0 4

I-Aiz

a.)

0t 6 2 3i5 67 8 DAYS FIG. 1. (^) DISAPPEARANCE OF RADIOIRON FROM MICE OF GROUP N GIVEN VARIOUS AMOUNTS OF THE LABELED IRON AS (^) FESO, ORALLY AS A SINGLE DOSE. Each curve is the average of four mice and the doses of iron administered were: w 0.6, * 5, A 10, N 25, * 50, 0 100, zv 500, <2 1,000, Cl^ 2,000, and^ A^ 3,000 ng.

amount of radioactivity in the animal at that (^) tipne and from the specific activity of the dose (^) given.

RESULTS

Disappearance of labeled iron from the body

after a single oral dose. The disappearance of

labeled iron from normal mice (group N) after

oral administration is shown in Figure 1. It will

be noted that the general pattern of the disap-

pearance curves was qualitatively the same re-

gardless of the size of the dose; the amount of

labeled iron in the animal from a given dose fell

rapidly soon after administration and then de-

clined much more slowly after 24 hours. The

labeled iron lost was completely recovered in the

feces of the animals. After 4 to 6 days, the

amount of iron lost per day was from 0.5 to 3

per cent of the amount of labeled iron remaining

in the animal; this rate of excretion is equivalent

to the turnover of body iron in the mouse (13).

Less than 1 per cent of the labeled iron retained

in the animal by this time was present in the

gastrointestinal lumen. Therefore, the amount

of labeled iron remaining in an animal between

4 and 6 days after administration of a given dose

was considered to be the minimum amount of

345

KINETICS OF IRON ABSORPTION IN MICE

Since, in the initial stages of absorption, when

Fe- is large, FeA will be infinitesimally small and k, [X]^ [Fed4] is^ virtually^ zero,^ then

ki[FeL][X] =^ k2^ + k3[FeX] or

[X] _ k2+ k

[FeX] (^) k{[FeL] [3]

If [X]t is the concentration of total (^) enzyme or

carrier in the system, [X] =^ [X]t- [FeX].

Substituting for X in (^) Equation 3 and (^) transposing:

tXI~t k2+ k3^ [4]

[FeX] ki[FeL] If a carrier or enzymatic mechanism is responsible for (^) absorption of iron, the maximum rate of absorption or the maximum amount absorbed, A, per unit time will be proportional to [X] +

[FeX] or [X]t, and the actual rate of absorption

or the actual (^) amount absorbed, a, per unit time will be proportional to [FeX] (15). These rates may be expressed, however, as amounts absorbed, A and a, if it is considered that within each group of mice the time of exposure of the dose to (^) the intestinal mucosa is the same for each mouse. In support of this assumption was the observation that in a given group of mice the transit time of the administered oral dose through the gastrointestinal tract appeared to be the same for the (^) different doses of iron, although the transit time of the different doses of iron through the duodenum and jejunum, where the greatest ab- sorption of iron would be expected to occur, was not known:

[XI1t _^ A^ _^ k2 + k3 (^) [5] [FeX] a^ ki[FeL] Substituting [D] for^ [FeL] and K^ for^ (k2 + k3) /k, in^ Equation^5 and^ dividing^ both^ sides^ of^ the equation by A, the result is, as expected, a form of the Michaelis-Menten equation:

(^1) =K I__ (^) 6] a A (^) ED] )+A[

Plotting 1/a vs 1/[D] should, therefore, yield a straight line. Plotting 1/a vs 1/D, the curve obtained from the data for the group N mice was indeed linear (Figure 4). The slope of this line, (^) however, was not K/A but (K/A) (1/C) where (^) C was

0 / 2 0 6/ 02

FIG. 4. PLOT OF THE RECIPROCAL OF THE AMOUNT OF IRON ABSORBED (^) (1/a) VS THE RECIPROCAL OF THE (^) AMOUNT OF IRON IN THE DOSE (l1D). Note that there is a differ- ence in the coordinates in each figure; the figure on the right includes an expansion of the origin of the figure on the left for the normal mice, group N. N = Group Fe., 0 =^ group N, and^ =^ group D,.

the volume of the gastrointestinal contents into which D was distributed. This was a consequence of plotting 1/D rather than 1/[D]:

1 KI 1 1 a A C D} A [7]

It would appear then that the absorption of iron in the group N mice could be described by two processes operating simultaneously. 1) A first-order process indicated by the linear rela- tionship between the size of the dose and the amount absorbed as described by Equation 1 with A equal to zero. In this system, the amount of iron absorbed per unit time would be limited by the amount of (^) absorbable iron in the (^) gastrointes- tinal (^) lumen that is presented to the absorbing surface and the upper limit would be determined by the size of the lethal dose. 2) A process which appears to fit the kinetics of an enzymatic or carrier process in which the amount of (^) enzyme or carrier in the (^) system would be the limiting factor for the maximum amount of iron absorbed by this mechanism.

Effect of variations in body iron stores upon

absorption of labeled iron. In mice of group Fe, the (^) expansion of (^) body iron stores with subcu- taneously injected iron resulted in two differences in iron (^) absorption compared with that in group N mice: 1) the amount of iron absorbed was proportional to the size of the dose so that a carrier or (^) enzymatic process could not be detected with (^) certainty; and (^) 2) the fraction of the dose that (^) was absorbed with first-order kinetics was

2-

/ 0

347

6,L

DAVID GITLIN AND ANDRE CRUCHAUD

TABLE I Constants for iron absorption in normal mice, in mice on

iron-deficient diet, and^ in^ mice^ given iron^ subcutaneously

Enzyme- or carrier- First-order limited process process Per (^) cent Group (^) A* Kat of dosel

D, 3.5^ 18.6^ 3. N 1.6 11.0 2. Fe. 0.45^ 7.3^ 1. Fe 0 0.

  • (^) Obtained graphically as the intercept on the ordinate when the linear portions of the absorption curves in Figure 3 and 5 were extrapolated to zero iron dose (cf Equation 1). t Ka =^ K/C. As^ indicated^ in^ Equation 7, the^ slope of the straight lines in (^) Figure 4 obtained (^) by plotting 1/a vs 1/D, was the constant K/AC. Multiplying K/AC, ob- tained from Figure 4, by A^ yielded K/C or Ka.

I The^ slope^ of^ the^ linear^ portions^ of^ the^ absorption^ curves

in Figures 3 and 5 multiplied by 100 per cent.

somewhat decreased (Table I and Figure 5).

Depriving mice of food for 24 hours prior to oral administration of labeled iron, as in group (^) Fe., did

increase the amount of iron absorbed by both

processes (Table I and Figure 5) compared with

group Fe.

In those mice kept on an iron-deficient diet

(group D8), the fraction of each dose of iron

absorbed by the^ first-order process was^ somewhat

increased over that for the group N mice (Table

I and Figure 5), but the amount of iron absorbed

by the enzymatic or carrier process was increased

to a^ greater extent. The mice in groups (^) N,8 and (D + Fe)8 ab- sorbed the same amount of iron at the doses

tested, and^ the^ amount^ of^ iron^ absorbed^ from^ a

given dose was only slightly greater than^ that

0 946W " CM /cW 0 40 mo^ ,90o 0)oir of^ ZPON (^) -//&. DoJt- of I'2/0N (^) -IU6. FIG. 5. THE AMOUNT OF IRON ABSORBED FROM A GIVEN DOSE OF IRON ADMINISTERED ORALLY. (^) Figure on (^) right is enlargement of^ area^ about^ the^ origin of^ the^ figure on^ the left. = Mice on iron-deficient (^) diet, group D.; - - = mice on^ normal^ diet, group N; * =^ iron-loaded^ mice, group Fe.; and Ed =^ iron-loaded^ mice, group Fe.

absorbed by the mice of the group (^) Fe, for the same iron dose. Effect of variation in body iron stores (^) upon absorption of labeled (^) copper. While increasing the body stores of iron drastically reduced iron absorption, the subcutaneous injection of 25 mg of iron did not affect (^) the absorption of copper. The relationship between the amount of copper absorbed and the size of the copper dose was the same for the mice in both group (^) Ncu and group Fecu (Figure 6). Neither the first-order ab- sorption of copper nor (^) the enzymatic process for copper absorption was influenced by the ex- pansion of body iron stores.

1ZZ

K.

ZZ:

2

/

(^20 40 60) do Doiorz^ /& FIG. 6. ABSORPTION OF COPPER AFTER ORAL ADMINIS- TRATION. 0 = (^) Normal mice, group Ncu; and * = (^) iron- loaded mice, group Fecu.

DISCUSSION In the mouse, as in man, an increase in the size of the oral dose of iron (^) results in an increase in the amount of iron (^) absorbed but a decrease in

the fraction of the dose absorbed. The data in

this study suggest that iron absorption in the

mouse is mediated by two different mechanisms

which operate simultaneously: 1) a process with

enzymatic or carrier characteristics in which

the limiting factor appears to be the amount of

enzyme or carrier available, and 2) a first-order

process in which the limiting factor (^) appears to be the amount of absorbable (^) iron in the gastro- intestinal lumen that is presented (^) to the ab-

sorbing surface.^ In^ the^ mouse, the^ process with

enzyme- or carrier-limited kinetics would appear

to have the major role in the absorption of iron

at dose levels of iron comparable to those in a

-I- -I- -1^ I- ..

348

klo^0 /oo 120

DAVID GITLIN^ AND^ ANDRE^ CRUCHAUD

doses of inorganic iron in human subj ects. J. Lab. clin. Med. 1958,^ 52,^ 335.

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