From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
STUDIES
OF
PHOSPHORUS
PERMEABILITY
PHOSPHATE
B
F.
IN
H.
L.
TAYLOR,
T IS A distinct
this
R.
technical
on
Minot.
use
It was
OF
assistance
under
first
M.
AND
KENDRICK,
that
A.
THE
ADAMS,
BA.
of articles
from
studies
to Dr.
physiologic
our
(P32)
B.S.
of a series
in human
direction
OF
INORGANIC
PHOSPHATE
published*
isotopes
his
A STUDY
TO
M.D.,
of MARY
the
of radio
II.
RADIOACTIVE
LEVEN5ON,
to dedicate
the
MAN:
ERYTHROCYTE
USE
S. M.
Pis.D.,
the
IN
HUMAN
BY THE
pleasure
laboratory
George
THE
VITRO
H”ith
I
METABOLISM
OF
venture
into
this
field
was
undertaken.
Radio
phosphorus
phorus
metabolism
Kamen.3
of the
Most
by use ofdosages
Human
studies
of the
the
tracer
Since
doses
the
body
metabolic
use
of
p32
methods
described
in
of phosphorus
to
exchange
added
to
amount
blood
and
calculated
may
been
the
red
may
Thorndike
was
two
amounts.
in number,
deranged
the
and
most
therapeutic
uses
by
metabolism
imposes
larger
of
than
of phosphorus
and
phosphorus
and
entered
They
also
present.
the
cell
the
ioi
stated
that,
in the
cells
Their
mg.
under
out
of
in vitro
to
while
human
at 7 C.
phosphorus
their
were
experimental
of proportion
observations
concentrations
an
added
freely,
resoluof the
phosphorus
in
were
were
phosphorus
be
distribution
of the
cells
to
the
of
will
was the
plasma
and
shown
p32
red
experiments
accumulated
phosphate
with
revisions
These
with
studies
et al.,#{176}
have
together
their
bood.
of whole
in in vitro
Eisenmann
of
technics.
is concerned
plasma
phosphate
In
problems
of counting
on phosphorus
metabolism
exchange
between
cells
media.
communication
the
Cancer
I of this
tracer
few
the
and
2
to
made
the
on whole
compounds
were
hematocrits.
which
and
be
to investigate
communication
cells
minimal.
present
work
present
was
p32
Hospital,
to
‘
in animals,
be considered
are
of phos-
Hevesy’
obtained
directed
immediately
at 38 C. phosphate
plasma
phases
by
amounts
processes
that
using
were
in tracer
having
of value
inorganic
radio
of various
summarized
ofwhat
p32
in the attack
of phosphorus
of inorganic
This
of
metabolic
these
ml.
100
conditions,
American
*
No.
been
using
P’2 as a tracer
in doses
low enough
to cause
no demondisturbance.
These
studies
wil
be presented
elsewhere.4
The
The
which
blood,
whole
From
in excess
concentrations
between
system
City
examination
have
in the literature
authors
between
exchange
In
presented
it seemed
such
blood.
circulating
by the
data
first consideration
the controversy
of
the
in the
and further
considerations
of accuracy
fully
in another
communication.5
The
tion
results
normal
of P3,
human
strable
used
the
of previous
isotope.
in
been
of isotopic
p32
the metabolism
on
interest
has
and
was
Memorial
the
aided,
Society
series4
part
by gifts
in
from
was
the
specific
Second
and
of Medicine,
(Massachusetts
is
phosphate
since
Laboratory,
Department
in
no
negligible,
Harvard
Smith,
Division)
Kline
Fourth
Medical
& French
to Harvard
preparation.
1472.
added
activity
except
Medical
School,
represented
isotopic
Services,
Harvard,
sodium
Boston
Boston.
Laboratories,
University.
that
of the
Philadelphia,
and
the
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
F.
phosphate
been
H.
used
L.
was
extended
TAYLOR,
very
S.
high.
to similar
M.
LEVENSON,
The
studies
in
AND
vitro
in vivo
M.
studies
in man
A.
ADAMS
presented
which
will
1473
in
this
paper
be presented
have
elsewhere.4
METHODS
Blood
from
normal
human
subjects
was
collected
in bottles
containing
dried
potassium-ammonium
2. Gm. of potassium
in distilled water to a volume of 100 ml . For each ml. of blood, 0.04 ml . of the anticoagulant
was
used.
Such an oxalate
mixture caused no change in cell size. p32* in the form of sodium
phosphate
solution
was added to the whole blood, the volumes of the radio-active
phosphate
solution
varying
from o.8 to 2.08 ml. per 100 ml. of whole blood, with activities
of PH varying
between
900
and
I2.,OCO
counts per second as registered
on our counter.
Samples
of the radioactive
phosphate
solution
added
which
oxalate
solution
oxalate
by dissolving
utilized
were
ments
as standards
to correct
geometry,
the
about
total,
was
the
Blood
saline
32
drawn
technics
date
sodium
with
and
inorganic
prepared
determine
the
dried
pendent
on
the
amount
fraction
of both
plasma
filtrates.5
and read
Inorganic
and Subbarow.8
from
this
solution
The
to
and
or minus
the
results
are
reaction
of the
direct
was
Tracerlab,
10
by
cells
was
for a period
was
again
of
instance
determined;
in plasma
the
the
were
then
plasma
blood
and
red
blood
the
red
blood
from
cells
were
centrifuged,
frozen
at
For
for each
washed
and
the
in
order
C.
-2.0
complexes.
was
analysis
once
supernatant
to produce
the
frozen
cells
The
exact
determination.
determined
with
and
by the
sulfuric
and
Subbarow’s
phosphorus
present
and
autoscaler.
to the
blood.
The
was
colorimetric
nitric
method
measured
calcium
phosphate
to measure
corrections
the
molyb-
acids.
Total
acid
in trichloracetic
and
size
cells,
of the
acid
trichloracetic
samples
of the
calcium
chloride
redissolved
in
acid,
that
estimated
methods
de-
soluble
acid
and
by
samples
taken
phosphorus
thickness,
the
acid
as described
of radioactive
film
were
was
total
with
was
samples
samples
of the
in dried
geometry,
was
plasma
The
concentration
for
It
p325
in
radioactivity
by precipitation
determined
of
cells
digestion
tube
Certain
one
of
several
activities
Monsanto
Massachusetts.
ways,
either
compound
than
experiments
Chemical
the
as
and
protein
used
were
in the
volume,
accurate
to
number
despite
Company,
per
percentage
of the amount
of 32 added
the per cent of the added amount
of 32
ml. of plasma cells or whole bloods, The
the
by dividing
obtained
phosphorus
P3 rather
of the different
Boston,
and
corpuscles.
in order
of the given
supplied
of plasma
per cent.
in
of added
blood
corpuscles
was
or as specific
percentage
comparison
* 32
t
red blood
expressed
flask,
by the milligrams
use
to
separate
required
by Fiske
added
all estimations
to
cent
red blood
fractions.
cells
water
by
determined
originally
dried
applied
red
Geiger-Mueller
fraction.
5 per
hematocrit
and
were
deter-
and
shaking,
chemically
to
chemical
plasma
C, and in the fourth
the
phosphorus
of distilled
and
The precipitated
were
washed
gentle
of
as possible,
of radioactive
the
and
phosphorus
made
were
plus
amount
of 32
frequent
phosphate
rpm
sample,
in both
phosphorus
hours,
2.000
initial
made
determined
corpuscles
and red blood
with
total
with
p32,
these
The
preceded
were
phosphorus
Fiske
inorganic
plasma
plasma
total
simply
all
of organic
Subbarow7
phosphorus
from
the
of four
at
solution.
same
were
at a temperature
were
in
amount
the experi-
tube
elsewhere.5
of both
Fiske
place
red blood
the
described
are
with
contact
minutes
hydrolysis
throughout
a Geiger-Mueller
In this
of
content
off as completely
The
diluted
of
and
To
discarded.
and
at intervals
with
blood.
32
for ten
oxalate
counted
phosphorus
measured
chloride
any
the
to
phosphorus
drawn
to prevent
phosphorus
method
filtrates
centrifuged
cent
32
took
was
were
inorganic
the
inorganic
ofammonium
performed
at 7 C. At the end
hours
was
and
total
soluble
and
incubation
and
were
employed
The
this
for four
off and
and
thawed
were
cases
plasma
per
0.9
hemolysis
soluble
concentration
The
cold
second.
experiments,
soluble
samples
corpuscles.
with
of the
kept
acid
and
acid
and
was
accomplished
per
3 Gm.
with fixed
by the use of an autoscaler.t
The background
count
in this
In none of these experiments
was there any count
lower
than
samples were removed for the determination
of the hemato-
Counting
in the initial blood sample.
was then allowed to stand in
total
cells,
of p32
dissolving
In all experiments,
the addition
of
after
In three
blood
the
experiment,
each
counts
total
In two
hours.
for
was
0.2.3
minutes
also measured
The blood
by
totalizing
of total,
corpuscles.
prepared
decay
background.
five
nunations
four
the
averaged
the
times
crit
for
and
laboratory
ten
was
100
of counts
variation
Clinton
as the
in the
basis
actual
Laboratories,
of calculation
amount
Oak
of
32
Ridge,
permitted
added.
Tennessee.
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
‘474
PHOSIHORUS
METABOLISM
IN
MAN.
II
RESULTS
Distribution
of Phosphorus
The
data
tween
red
range
of
ments
I,
are
in
cells
those
and
normally
3)
phosphate
There
presented
blood
2.,
Fractions
was
was
no
increase
incubation
unchanged
the
be
observed
hours
that
cells
errors
plasma
content
of Phosphorous
plasma
the
between
of the
employed.
forms
of phosphorus
slightly
or remained
present
in all samples.
Plasma
(5 minutes)
of any
methods
of all of the
2ompounds
be-
were in the
at 37.5 C. (experi-
and
of
distribution
blood
The hematocrit
increased
Minimal
hemolysis
was
experiment.
the
incubation
between
experimental
of the
Er,ythrocytes
nonincubated,
four
exchange
Initial
E
and
initial,
After
net
I . -DistriLution
‘IBLF:
It will
i .
proceeded.
during
Plasma
on the
beyond
a slight
as
table
plasma
accepted.
there
compounds
studied
between
and
After
Erythrocvtes
4 hours
incubation
I Tissue
T
I
#{176}‘
C
tr
Plasma
37.5
Red
37.5
m
.
Inorganic
I’tTotal
acid sol
mg. per 100 I uble P mg.
ml.
per 1(10 ml.
12.8
(74)
3.0
(1.71
41.8
0.1.4
(26.5)
7..)
(.3.1)
1.4.1
(7.4)
.3.1)
(1 .7)
43.2
57.5
(24.8)
6..)
(2.71
11.6
(6.3)
2.9
(1.6)
45.3
55.2
(25.11)
7.1
(3.3)
3.1
Hct.
(1.8)
38.8
T
I
Inorganic
mg.
I)
per
I per
43.0
acid solPt mg.
lOt) ml.
per
4.4
(2.5)
(22.0)
7.8
(3.3)
(8.7)
4.0
(2.3)
4.5
(2.5)
(25.1)
6.3
(2.8)
38.8
(16.5)
5.1)
(2.7)
5.6
(3.5)
33.2
14.7
(16.0)
Pt Total
uble
100
ml.
(8.4)
51.2
4.7
(2.7)
34.6
(14.9)
blood
2
Plasma
37.5
Red
blood
37.5
3.1
(1.7)
15.3
(16.8)
38.8
43.3
57.5
45.5
47.6
41.9
58.6
cells
Plasma
.17.5
Red
.17.5
3.
2.8
(1.5)
31.4
15.2
(14.3)
(8.3)
(21.7)
(3.1)
(15.2)
blood
cells
Plasma
7
8.7
(5.0)
2.2
(1.3)
Red
7
42.4
57.8
(24.5)1
8.3
(3.5)
in mg.
per
1(8) ml.
of cells
or plasma:
4.
I
2.3
(1.3)
38.7
9.3
(16.4)
(5.4)
(24.6)
2.1
8.1
(1.2)
2.2
(3.4)
(1.3)
45.2
(18.9)
blood
cells
.
Hct.
-Hematocrit
t Values
tribution
given
from
At
change
was
was
by
hour
the
The
data
inorganic
of table
known
dilutions
incubation
or
of red blood
that
in parentheses
are
at either
include,
i
as distributed
values
calculated
for
whole
dis-
blood
continued
or 37.5
in parentheses,
in whole
of
phosphorus
compounds
observed.
phosphate
during
was
both
7 C.
of the blood
was
distribution
cells
inorganic
fraction
in plasma
phosphorus
period
constituents
When
hematocrit
of the organic
phosphorus
incubation
phorus
in
hemolysis
no indication
the expense
Acid
soluble
error,
and
no
nor
There
figures
hematocrit.
7 C.,
occurred,
at
the
of the
red
blood
cells
four hours
of incubation
accounted
for, within
in the
initial
bloods
and
increased
at 37.5
the limits
after
the
C.
of
four
C.
a recalculation
blood
using
the
of the various
phosobserved
hematocrit
as the basis of calculation.
for
twenty
three
hours
at 37.5
C.,
a marked
in-
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
F.
crease
of
was
the
TAYLOR,
was
present.
plasma
data
L.
hematocrit
hemolysis,
in
H.
M.
found
LEVENSON,
cell
with
and
Concomitant
content
beyond
S.
of
an
incubation
Exchange
between
all
the
AND
of
A.
ADAMS
1475
destruction,
as indicated
by marked
this cell destruction,
marked
increases
phosphorus
period
M.
fractions
four
was
hours
have
found.
been
For
this
excluded
reason
from
this
communication.
Phosphate
The
of
data
the
are
added
cells.
presented
and
in table
was
32
These
Plasma
figures
or
represent
TABLE
the
2-Phosphate
Temp.
P’addedt
-a-
-
1.
Plasma
CJS.rer
Red
blood
37.5
2.
3.
4.
37,5
Redblood
37.5
Plasma
37.5
Redblood
37.5
.
In
two
and
methods
addi
T t I p+
0J32(7(of
-
-
-
-
-
8.961
(4.0)
57.2
(2.6)
43.6
addition
of the
(18.5)
6.7
on whole
second
blood
per
are
100
specific
.
(0.27)
distribution
ml.
whole
.
activities
the
were
. .
per
this
.
sol-
ubIePof
(13.c)
33.7
(12.8)
57.4
(12.5)
(3.9)
________
-
(4.1)
33.9
(Ia.6)
36.0
46O
(16.7)
52.2
(3.2)
-
55.7
(2.6)
49.8
(14.2)
57.8
(3.8)
-
-
101.0
(18.7)
97.7
(81.4)
101.5
(78.1)
-
-
2.9
3.2
(14.4)
(0.17)
-
2.6
(O.76)
I
data.
blood.
cent
of
--- -
#{182}7
of added
as
the
for
time
(012)1
I
calculated
determined
At
32
acid
(2.1)
I
experiments
activities
Total
51.6
mg.
specific
P
% ofadded
33.7
-
-
)
parentheses
incubation
Inorganic
I
(0.14)
92.0
per
red
3a.6
-
3.6
#{231}
940
cent
and
employed.5
4 hours
(
ofaddJI2
-
per
Erythrocytes*
After
-
j
calculated
in
the
.
)
i
t C.P.S.-counts
.
Plasma
Toaac1
Inorganic
_
11.640
:
Redblood
cells
Figures
between
of
io
plasma
______________
1
Plasma
All values
accuracy
and
91
the
in
I
Plasma
*
between
present
minutes)
ofaddeJ
9.620
cells
(5
I P
37.5
that
as
of
Exchange
T
be seen
determined,
limits
Initial
Tissue
It may
2..
recovered,
Erythrocyte
added
6.7
per
-
-
and
per
red
cent
-
10)) ml.
------
per
in
p32
plasma
3 .6 and
activity
----
of P compound
100 ml.
the
total
cells
five
were
phosphorus
minutes
found
in
and
after
the
red
the
blood
cells.
incubation
After
phosphorus
been
no
it had
been
washed
from
red
for
the
forms.
remained
four
hours,
about
plasma.
In each
inorganic
phosphate
the
When
in the
blood
plasma
was
in
one
instance
kept
inorganic
between
plasma
of
in the
and
the
third
the
the
residual
radio
there
acid
at 7 C. for four
fraction
added
plasma
had
soluble
hours
all of
in which
form
added.
C. the
At
rapid,
organic
also
32
C.
in
between
or other
added
37.5
detected
turnover
organic
the
at
was
i
cells
exchange
to
57
at
four
per
of phosphate
cent
hours.
of
the
added
radioactivity
and
red
being
blood
detected
cells
in
was
the
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
1476
PHOSPHORUS
Most
From
of
soluble
to the
was
of the
in the
inorganic
of the
and
not
was
in the
that
fractions.
activities
in
the
II
the
acid
soluble
organic
phosphate.
fraction
in
four
At
7 C. essentially
plasma
fper
hours
in the
at the
cent
In
in
vivo
of
falling
in vitro
end
of the
there
acid
was
all
any
of the
added
pa in plasma/
isotope
in R.B.C.\
added,
i ranged
.
five
be seen
that
or exceeds
that
hours.
p32
on
will
equals
of the
added
studies
it
2.,
cells
of four
this ratio
for obvious
p32
table
of the
of percentage
i --\per cent
1.5.
in
phosphate
in terms
plasma
of
presented
inorganic
of 100-2.00
microcuries
level of p32 was rapidly
duplicated
of
found
indication
organic
specific
and
a mean
no
MAN.
fraction
was
p32
soluble
of the
cell
with
1.7
There
of the p32 activity,
red blood
injection
plasma
inorganic
added
fraction
ratio
the
IN
form.
activities
inorganic
The
in
of the
nonacid
a study
specific
the
was
phosphorus.
From
the
p32
per cent
14
exchange
p32
the
6 to
METABOLISM
normal
between
men
was 6.4.
physiologic
In
between
five
these
reasons
i
hours
.
after
instances
which
the
were
experiments.
DIscUssIoN
The
data
presented
workers6
that
hours
at 37.5
entrance
tion
of the
of
plasma
marked
Based,
and
washed
red cells,
by
hmolysis.
on
beyond
In the
hemolysis
of
the
cells
changes
four
did
text
red
differ
plasma
slight
hemolysis
data
they
they
cell.
longer
is
worth
distribution
from
concentration
indicate
that
of
of all the
the
red
that
blood
while
fraction.
under
was
over
of organic
It is well
glucose
rapidly
glucose
is very
the
to or greater
known
the organic
utilization
at
carried
by
the
twenty-three
the
The
derivatives
been
vitiated
in
hours.
by
destruction
had
that
both
to the
precluded
were
compounds
phosphorus
in
remaining
slight
increas:
is presumably
due
to
o
per
cent
than
the
of
added
cent
entered
p32
was
found
been
present
in
of the red blood
specific
retention
cannot
the
per
i
activity
of the
of phosphate
be entirely
the
in
the
cell
plasma
in the
accounted
red
at
C.,
the
red
acid
inorganic
inorganic
inorganic
blood
for by
cell
the
complexes.
that
falls,
slow.
studies
at four
co-
cells.
Therefore,
penetration
and
these
experimental
conditions
formation
to
equal
were
in its
mentioning
blood
cell at 37.5 C. in four hours,
less than
soluble
organic
fraction,
the remainder
having
fraction.
At this time
the specific
radioactivity
fraction
studies
phosphorus
p32
is permeable
culminated
so obtained
obtained
her
concentraof
cell
incubation
data
while
those
phosphate
red blood
which
of the
and
within
a period
of four
any criticism
that
the
determinations
incubation
cell
indicated
C. Most
It
the
cells
from
increased
direct
that
blood
of Eisenmann
to the
on
show
red
it was
markedly
of
statement
red blood
are free
due
are,
that
the
at 37.5
intracellular
not
in the
The
in
hours
the
the
was
as
It is unfortunate
physiologic
hours,
phosphate
plasma.
ion.
confirm
readily
enters
the
present
investigations
the
phosphate
the
amply
phosphate
C. The
when
while
when
It is possible
acid soluble form
of glucose
by cells.
whole
blood
plasma
that the
is incubated
or
serum
transfer
may
be due
This
point
to
is
are
incubated
of phosphate
from
phosphorylation
being
37.5
so
further
the
the
the
which
investigated.
blood
fall
inorganic
precedes
of
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
F.
Additional
turnover
labeled
that
phosphate
amount
of
organic
S.
both
M.
LEVENSON,
the
inorganic
AND
penetration
to
acid
between
red
discovered
p32
blood
the
in
A.
ADAMS
organic
1477
cell
by phosphate
phosphorus
compounds
by a comparison
of the
latter
case no significant
cells
red
M.
of the red blood
soluble
of cell metabolism
is given
that obtained
at 7 C. In the
37.5 C. with
at
TAYLOR,
from
be functions
may
L.
evidence
the
and
H.
and
blood
plasma
cell
was
data obtained
exchange
of
occurred
confined
and
the
entirely
small
to
the
in-
fraction.
This
experience
gives
can be undertaken
in man
it will
permit
tissues
such
rise to the hope that
using the red blood
investigations
as the
liver
in vivo studies
cell as a tissue
of intermediate
are not
readily
phosphate
of phosphate
cell model.
metabolism
exchange
If this is so,
in man,
where
available.
SUMMARY
.
Phosphate
the
form
I
in
No
2..
high
exchange
of sodium
phosphate
specific
in
acid
was
in the
soluble
5
The
.
added
plasma
other
than
the
was
isotopic
exchanged
freely
studied
in
vitro
preparation
using
which
the plasma
transfer
occurred
the erythrocytes
32
was
of
fraction,
less
and the erythroat 7 C.
during
this time
between
offour
hours.
Minimal
p32
which
passed
into
inorganic
specific
of the
and
than
i
5 per cent
being
found
in the
organic
fraction.
to or greater
end
cells
as a tracer.
activity.
3 . Inorganic
phosphate
cytes at 37.5 C. in a period
4. Most
of the added
remained
red
phosphate
than
four
activity
of the
that obtaining
hour
inorganic
for the
incubation
period
phosphate
inorganic
at 37.
of the
phosphate
erythrocytes
of the
was equal
plasma
at the
C.
REFERENCES
G.
1 HEVESY,
7:
2
iii,
applications
Applications
-:
M. D.
3 KAMEN,
of radioactive
of radioactive
:
Radioactive
indicators
in
turnover
studies.
Advances
indicators
Tracers
in biology.
in Biology.
New
Ann.
York,
Rev.
Biochem.
Academic
9? 641,
Press,
M. A., FLUHARTY,
R., AND TAYLOR,
F. H. L. : Studies
olism in man. III. The distribution,
excretion
and exchange
of phosphate
radioactive
phosphorus
(P’2) as a tracer. (In preparation)
ADAMS,
M. A., LEVENSON,
S. M., FLUHARTY,
R., AND TAYLOR,
F. H. L. : Studies
S. M.,
4 LEVENSON,
5
: Some
olism
(In
in
man.
Enzymology,
ADAMS,
I. Methods
for
the
determination
of radioactive
phosphorus
Inc.,
1940.
1947.
in
phosphorus
in
man
in
phosphorus
(P32)
metab-
in
vivo
using
metab-
in body
fluids.
preparation)
6 EISENMANN,
erythrocytes
Biol. Chem.
FISKE,
in
1947.
C. H.,
A. J., OTT, L., SMITH,
P. K., AND WINKLER,
A. W. : A study of the permeability
to potassium,
sodium and inorganic
phosphate
by the usc of radioactive
i3j.’
i6, 1940.
AND
SUBBAROw,
Y.: The
colorimetric
determination
192.5.
AND-:
Phosphocreatine.J.
Biol. Chem.
81.’ 62.9,
192.9.
of phosphorus.J.
Biol.
of human
isotopes.
Chem.
J.
66: 375,
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
1948 3: 1472-1477
STUDIES OF PHOSPHORUS METABOLISM IN MAN: II. A STUDY OF THE
PERMEABILITY OF THE HUMAN ERYTHROCYTE TO INORGANIC
PHOSPHATE IN VITRO BY THE USE OF RADIOACTIVE PHOSPHATE (P32)
F. H. L. TAYLOR, S. M. LEVENSON, M. A. ADAMS and MARY KENDRICK
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