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Studies
V. The
By
EUGENE
of Cobalt
on the
GOLDWASSER,
OR
NEARLY
erythropoiesis
for
0.
cobalt
a
exerts
that
cobalt
marrow,5
while
later
the
formatiots
by
produce
a
itsdirectly
acts
have
does
therapeutic
Its a
effect
and
used
to
not
measures,
by
poietins
except
the
evideisce
is used
accelerates
toxicity
to
of
productiots
designsate
erythropoiesis
the
whens
the
This
linsits
that
are
factor
such
However,
nsarrow
attetsspts
its
ins vitro
seensing
synthesis
in
found
plasnsa
ANI)
previous
in plasnssa
is injected
This
paper
reports,
the
of
ansenssic
into
of
has
applicability,
to
all
assay
it
the
or elinsinsations
of the unsderlyinsg
data
indicating
that
cobalt
As
either
at. a
paradox
clinical
refractory
of erythropoietin.
finding.
MATERIALS
A ssay
of cobalt
‘
ins tise
oss the
by the use of cobalt,
has showns
that
cobalt,
depresses
anemias
coisditioss
effect
coissplexes.#{176}
experinnetsts.9
transfusions
we presensted
this
aisoxic
nsarrow
study
respiration,
certains
paper,!O
stimulating
further
affect
in short-terns
correct
preliminsary
acid
of
that
cohalt
inscreases
chloride
given
orally
ass atsoxic
indirect
the
failed.#{176}A receist
respiration
ANt)
insduces
and
tnaintainss
a polyThe precise
nsechansisnn
by which
Clarified
comsspletely.
Early
studies
produciisg
an
of cobalt-ansinso
hemoglobin
from glycine
not yet been resolved.
Although
the appreciable
been
weeks
by
FIIIEn
WALTER
1LZAK
animals.
yet beens
suggested
ins
or directly,
that
JACOBSON,
F.
several
directly
work
depression
concentration
has
of
man
itsdicated
(‘aused
period
of Erythropoietin
it has beets
knsowns
animals.’
Cobaltous
ansd experimenstal
this actions
has not
in
Production
LEON
three
decades
its experimental
parenterally
cythemia
to
Erythropoiesis
LOUIS
F
or
Effect
on
usual
disease.
exerts
its
gives
term
details
erythro-
ansinsals
that
ansinsals.
METHODS
Animals
Starved
on hypophvsectomized*
rats were used to assay
thse various
prepanationss
for erythropoiet
in activity
as described
ins previous
assay method
measures
the per cent of injected
Fe59 that is incorporated
standardized
conditions.
A minimum
of 5 rats was used in cads assay
Preparation
of “Cobalt
expermnsenstal
pubhcat
ions.”-’2
insto red cells
plasma
Thse
tnnsder
group.
Plasma”
Aliquots
of a stock solution
of cobaltoiss
chloride
(0.025 M) were inijected
subcutaneously
insto rats asd rabbits
accordinsg
to the schedules
described
for cads
separate
expeninsent.
After the indicated
intervals,
the treated
ansimals
were bled by cardiac
puncture,
the plrLsnsa
was separated
and, if not used immediately,
Was
stored at - 18C. %Vhens Co6#{176}was mssed, it
was mixed
withs aliquots
of the stock solutions
before
injections.
Plasnsa derived
frons aninsals
A preliminary
report
of some of these findinsgs
has beems punh)lishe(l.’#{176}
From
the Argonne
Cancer
Research
Hospital,
USAEC,
and the l)epartments
chemistry
amid Medicine,
The University
of Chicago,
Chicago,
Ill.
Submitted
May 6, 1957; accel)ted
for pmnl)lication
Sept. 20, 1957.
* Obtained
from Hormone
Assay
Laboratories,
Chicago,
Ill.
55
of Bio-
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56
5TUI)IES
I -Effect
TABLE
of
(‘obaltous
ON
Ion
the
on
V
ERYTHROPOIESIS.
Incorporation
of
Hypophqseclouiized
Fe#{176}into
the
Red
Blood
Cells
of
Rats
#{182},;
of Fe#{176}#{176}
Incorporated
Normal
................
Plasmna
2.1
Co
*
Stansdand
deviat
2.-Effect
‘I’ABLE
iO!i
of
t Ise
of
(‘oball
of
3.8
±
2.0*
9.5
±
4.9
nsean.
Plasma
on
Hypoph
ysectomized
the
In(’orporation
and
of
Fe59
Normal
into
the
Red
of
(_
2.6
19.4
...........
Cobalt
Plasma
insjected
with
previously
toxic
Effect
of (‘obalt
The
direct
insjectinsg
effect
1 nil.
tions
as
of
iron
into
red
constaininsg
0.6
26.7
±
9.2
±
7.4
35.6
±
1.1
plasnna.”
Exactly
the same methods
the amotnnsts
used being
limited
This
by
were
the
1.05
of Fe59 into
j.moles
each
red cells
day
was
for
2 days
by
studied
into
hy-
the
incorporations
of Fe’9 as in the standard
assay.
2.1 Mmoles of cobaltouns
ion stimulate
the incorpora-
deternining
1 reveal
cells.
±
of Fe5#{176}
solutions
thens
ins table
that
finsding
nsecessitated
the
misc of
cobalt-contaimsimsg
controls
l)eIO’IV.
of Cobalt
Cobalt
Gmss. donor
were
Norman
ions on the inscorporationi
a cobalt
shown
described
Eff(’Ct
of cobaltous
of
rats,
results
“cobalt
examine(1,
is termed
on the Incorporation
pophysectonsized
The
cobalt
for the other
nssetal ionss that
action
of each metal.
insed
Cells
Fe#{176}#{176}
Incorporated
Hypophysntomized
Salinse
Blood
Rats
Plasma
plasma
was
rats which
pophysectommzed
takable
stinsulatiors
on the Incorporation
l)rodumced
by
were sansspled
experiment
aninsals
Time
reveal
ansd the
Course
The
tinsse
aniinssals
was
tiois,
of
:usd
irons
solutions
plasma
of cobalt
into 400assayed
in by-
was
course
of
ensoughs
tniinsals
the
the
proportionality
of necipienit
Erythropoietin
deternssimsed.
with
of tlse stock
This cobalt
incorporatmons
a rom,ghs
response
of
rats
6 ml.
later.
results
shown
in table
2. There
was
an unmisby tise cobalt
plasma.
By mixiisg
Co6#{176}
with the
stock
solution
of CoCI7
tusd nseasmmninsg the amousmst of isotope
remaininsg
in the plasma
after
24 hsotnrs, we were able to show that about
0.4 pen cent of the original
amoumst of cobalt
that
Isad l)eens injected
was pnesenst
ins the
4 ml. of plasnia
tisat was used for assay.
As might
be
insferned
from thie data
ins table
1, thsis amotnnst
of cobalt
(0.6 onsoIes)
is too snsall to elicit a
responsse
of the
!ssagnsitsn(le
seens in table 2, and the observed
enythropoietic
effect
was
therefore nsot attributable
to free cobaltous
ion. Similar
controls
will h)e describe(l
ins later expenimensts.
Thse relationshsip
bet ween
the enythnopoietic
activity
of cobalt
plasma
ansd the amousnst
of cobalt
insjected
insto donors
was
studied
with the results
showni in table 3. Three
hundredGnss. donsor rats were given
sinsgle insjectionss
of cobalt
solution,
with the exceptions
of the
hsighsest
dose
whsichs,
because
of its
toxicity,
was
given
ins a divided
dose, 2 hours
apart.
The
plasma
was
drawms after 24 hours
and assayed
in hypophysectomized
rats.
The data
from
this
ansd nsormal
injectinsg
18 hours
o,f Fe59
ansinssals
were
the
resulting
amount
of cobalt
cobalt
given
to donsor
plasma.
Production
of erythropoietie
appearance
Each
between
to the
donsor
bled
at
animal
was
each
tinse
activity
in
this
pla.snsa
of
domsor
given 75 j.smoles
of Co
in a single
injecinterval
to yield a mininsum
of 20 ml.
of
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GOLDWASSER,
3.-Effect
TABLE
of
4mount
of
Co
Injected
of
(A ssayed
5M
Co5
FItIEI)
JACOBSON,
%
Donor
Cobalt
Plasma
hypophysectom
in
Injected
into
of
0
ANt)
I’LZAK
Rats
ized
en.
.1 ctivity
Erythropoietic
rats)
Difference
Fe59 Incorporated
from
Control
2.6±0.6
37.5
8.0
±
3.3
5.4
75.0
10.6
15.9
±
6.1
3.1
8.0
150.0
±
13.3
0’
In
0
U,
I-
D
0
10
20
40
30
TIME
FIG.
1.-Time
represents
course
the
plasma.
The
average
cobalt
of
erythropoietins
of values
plasmas
formation
obtained
were
50
from
then
60
70
80
(HOURS)
assayed
after
a group
in
cobalt
of 5
starved
stimm,lation.
assay
rats
Each
poiist
rats.
with
the
resmilts
showss
in
figure 1. After a lag period
of about
4 hou,rs, there
was a sharp
rise irs the content
of erythropoietin
in the cobalt
plasma.
The maximmsm
titer
was reached
at abomst 12 hours.
A curve
derived
from these
data could
be indicative
of the action
of either
of two mechanisms.
A
storage
site of the hormone
may be stimulated
for a short
time to produce
the factor,
at
an accelerated
rate, which
has a short
half-life
in the plasma.
This explanation
seems
less
likely
in view of the lag period
and, more importantly,
the kisowis effect
of cobalt
ins producing
a true polycythemia.
Further
evidence
that cobalt
exerts
its effect
by stimulating
synthesis
is
with
cobalt,
ever,
the
hours
later,
of cobalt.
That
of cobalt
amount
Co6#{176}
as
to be in
provided
the
animals
the
by
additional
enythnopoietin
were
titer
given
rose
data
titer
to
of the
another
abomst
showing
that
plasma
had
injection
the
same
of
level
72
homnrs
returned
cobalt
as it had
and
after
ais
initial
to
coistrol
levels.
tise
plasma
was
6 Isomsrs
after
the
first
stimuluns
If,
how-
sampled
6
injections
the effects
of cobalt
plasma
as seen in figure 1 were hot caused
by residmnal
amounts
ins the plasma
can be seen by examining
tise curve
Issanked
cobalt
control.
The
of cobalt
present
in the plasnia
was determined
by means
of
a tracer
quantity
of
described
above.
An amomint
of utnlabeled
cobalt,
calculated
from the Co6#{176}
conteist
the plasma
at each time interval,
was then mixed
witis normal
plasma.
This plasnsaplus-cobalt
was used
as a control for cobalt plasma
containimsg
the same amoumnt of the ions.
The stimulated
isscorporations
of Fe59 seen were, therefore,
nsot (line to cobaltomss
chloride.
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58
STUDIES
TABLE
of
4.-Effect
Iet
ON
Metal
EIIYTHItOPOIESIS.
Ions
on
V
Formation
of
Amount
Donor
I .Salt
Plasma
Erythropoietin
%
Injected
into
Rats
(jiM)
MnsSO4
NiCI2
of Fe59 Incorporated
by Recipient
Rats
186
4.5
±
0.9
114
3.4
±
0.5
317
3.9
±
0.2
Fe504
57
3.8
±
1.0
Co(NH3)6Cl3
57
8.7
±
2.0
CoCI7
57
11.9
±
3.2
Salinse
-
4.6
±
0.6
Fe’4
Animonsiuns
Tlse
Citrate
l)ossibilmtv
for
vitnssains
founnsd
that
has
been
the
two
conspletely
cobalt
plasma
accunsuilated
(Obalt
thse Plasnsa
Ins additions,
forns
of B,7 does
that
ins lange
l)l55155It5
is,
proteinss
by either
extracts
of
part,
heat
boths
free
cObaltoUs
that
that
be
possible
in plasma
of the
gross
from
retainsed
after
types
When
precipitation
of
of
have
erythro-
whether
active
both
iii
the
the
Evidence
principles
contained
denatunrations’5
or by precipitation
of 1tsnssa retains activity
after
we
animals.
of the
activity
ansd
determine
anemic
properties
erythropoietic
of Fe59.
to
be
may
qununtities
ansimals,#{176}
inscorporations
will
iou
microgram
hypophsysectomized
it
The
than
shown
nsot stimulate
some
similar.
has
in
characterized,
is identical
with
are
othier
Crafts
ons erythropoiesis
showing
of l)lasnssa
of cobalt
effect.
as 1.0 mg.
beens
types
some
erythnopoietic
nso effect
as mssuch
has
in
nsaterial
and
thse
1357 have
poietins
that
rensainss
responssible
major
in
anemic
portion
with perchloric
prolonged
dialysis
of
acid.
and
lvophsilization.
JfTec1
Bleeding
of
A sinsgle
l)lasnssa
ansinsal
bleedinig
enythropoietiis.
(300 Urn.)
us
each
instervals,
insstarved
repeated
on Lrjthropoietin
nsassive
by
groti
:tcts
this
cardiac
of
rats
rats (fig. 1). While
or after
aithousgis
(lie
blcedimsgs
cobalt
plasma,
Effect
f Other
Metal
Ions
Production
ins the
same
experinsenst,
mansnser
as
cobalt,
as
a stimuluis
to
blood
was
hematocnit
removed
of l)lasma,
and
the
plasma
the observed
stimssuluns
is considerably
cobalt,
it does follow a time course
less
than
that
l)msnsctuire,
was
ott
with
then
peak
of
8 ml. of
a resulting
bled
as
a sousrce
erythiropoietin
Erythropoietin
titer
is
from
of 27.
similar
reached
At
inscrease
each
the
to that
donor
indicated
assayed
seen
after
seens with
soonser.
Production
Thse effect
of otlsen
Iseavy
metal ionss, as well as that of a cobaltic
complex
ions, was studied
to deternsinse
whether
the stinstslations
of erythropoietin
synsthesis
was
specific
for cobaltouss
ion or, l)crhal)5,
duse to general
heavy
metal
toxicity.
The metal ions were chosen
because
of
their chsennical
or toxicologic
stimilanity
to cobalt.
The data in table
4 indicate
that other
toxic
heavy
nsetals
lsave no effect
ins stinssulating
the production
of erythropoietin.
Surprisingly,
cobaltic
hexamine
chloride
did have some effect,
which
may possibly
he due to
redunctions
of the complex
ions, hunt evidence
of this is not yet available.
DIsCuSSIoN
These
probably
caused
by which
nsism
the
data
mechamsism
would
anioxia,
suggest
show
that
the
erythropoietic
by ant inscrease
cobalt
by
that
increases
which
the
bleeding
production
effect
ins circulatinsg
production
or
of
produced
plasma
of erythropoietin
phemsylhydrazinse
erythropoietims
by
erythropoietins.
does
is
the
stimulated
cobaltous
The
ions is
mecha-
is as obscure
as
same
thing.
We
by a relative
and that
cobalt
nsay act by producissg
ans ansoxic
state
in the kidney22
rather
thans ins the bomse marrow.
These
finsdinsgs are of insterest
from the climsical point
of view.
If, as our studies
imsdicate,
the erythropoietic
effect
of cobalt
is based
upon
an inscrease
ins plasma
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
GOLDWASSER,
erythropoietins,
then
the
clinical
FRIED
usefulniess
of the
of disease
cotsditions
ansd
is reported
to be influenced
will favorably
imsfluence
the
a nunsber
anemia
Cobalt
ciency,16
chronic
renal
disease,’7
densonsstrated
that plasma
made
effective
its
producing
starved
plasma
rats,
from
nornsal
ansimals
sine.
The
rapidity
search
for
ats
gonads,
does
phenylhydrazine
mental
states.
not
In
cobalt
to show
with
erythropoietins
or elinsinates
or after
acute
response
to cobalt
known
that
the
diminish
(ansd
removal
productions
Extracts
activity
tsephrectomy,
production.
have
is as
mice2#{176}as
phensylhydra-
is importaist
FF0155
our
orgaiss
is
ins the
atsd
experiensce
of the pituitary,
of erythropoietims
that
thyroid,
adrensals,
us responsse
to
do not
yield
nsaterials
Because
of the rapid
death
that
follows
were
unsable to use the usual bleedimsg
or
of 85 to 90 per
Removal
the production
hemorrhage.22
are
rats,
polycythemic
beets givens
have
of various
either.2’
we
removal
There
and canscer.’t
We
by the use of cobalt
to phlebotomy)
schedule
to study
erythropoietin
preliminary
experinsents,
we
that
is obvious.
in hypophysectonsized
of erythropoietin.
or phetsylhydrazinse.”
with
erythropoietic
hepatectomy
and
hornsonse
experinssetstal
states
in which
the associated
beneficially
by the admssinsistration
of cobalt.
ansensia
of hypophysectomy,’4
proteins
defi-
erythropoietic
respotsse
59
PLZAK
chronic
inflamnsations,19
rich its erythropoietimi
of productions
it is already
bleeding
ANI)
rats,
and transsfusiots-induced
that have
been bled or that
of the
site
the
of others,
or
JACOBSON,
productioss
have
cent
of the
of both
of erythropoiet.ins
used
ins these
the
rapid
liver
does
kidnseys,
after
the
two
experi-
responsse
to
nsot insterfere
however,
suppresses
adnsiiniistrations
of cobalt
SUMMARY
It has
cobaltous
The
been
shown
that
chloride
rapidly
gross
treated
properities
as from
plasnsa
develops
of the
from
ansiinals
that
have
a high titer of erythropoietin.
active
material
phenylhydrazine-treated
appear
to be the
sanse
with
from
cobalt-
as stimulants
jots with
the
for eryt.hroexceptiots
of
hexamine.
SUMMARIO
Es
monstrate
cobaltose
que
disveloppa
Grossiermente
caso
itsjected
animals.
Other
metal
ioiss and a complex
ions have beeis studied
poietin formation;
none was as effective
as cobaltous
cobaltic
beeis
de
le
plasma
de
rapidemente
tractate
cons
INTERLINGUA
aisimales
un
le proprietates
animales
IN
subjicite
alte
titro
del
substanstia
cobalt
que
a injectionses
de
chloruro
de erythropoientinsa.
active
its
Ic
pare esser le mesnse
de ansinsales
tractate
caso
ins le
cons
phenyihydrazina.
Altere
formation
habeva
iones
metallic
e un
ion
complexe
esseva
studiate
de erythropoietina.
Nulle,
cots le exception
le mesme
grado
de efficacia
como Ic iois cohaltose.
como
de
stimulantes
hexamina
del
cobaltic,
REFERENCES
‘WALTNER,
2 SCHULTZE,
BERK,
with
K. AND WALTNER,
K.: Kobalt
M. 0.: Metallic
elements
and
L., BURCHENAL,
J. H., AND
or withommt anemia.
New
CASTLE,
England
und blut.
Kim.
blood formation.
W.
B.:
J. Med.
Wchnschn.
Physiol.
Erythropoietic
240:
724,
effect
1949.
8: 313, 1929.
20: 37, 1940.
Rev.
of cobalt
in patiensts
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
00
4
STUI)IES
W. C. ANn) itO()1’,
W.
449, 1952.
BARRON,
A. G. ANI)
BARReN,
ON
EItYTILItOPOLESIS.
S. : Fuindansental
GRANT,
V
stimulus
for
erythropoiesis.
Physiol.
Rev.
32:
S
acid.
ascorbic
6
D.,
BURK,
halt,
7
Proc.
ans(l
Arch.
C.
WARREN,
9
M.
LAFORET,
row
T.,
GomnwAssER,
I.
#{176}
lations
46:
‘
ANI)
TinosnAs,
Chsens.
671,
A. L. : Reversible
165:
723,
Effect
of
complexes
of
co-
1946.
col)alt-histidinse
complexes
I. H. : Stu,dies
WooD,
before
arid
after
of cobalt
on the
on heme
nsechansism
syisthesis
of cobalt
by boise
mar-
1955.
W.,
FRIED,
Science
AND
125: 1085,
L. 0.,
from
by plasma
polycythensia.
1936.
AND
BETHARD,
ansemic
L. : The
PLZAK,
nsechansism
of the
1957.
rats
W. F.: 1)emssonsstrations
of stimuusing Fe59. J. Lab.
& Chin. Med.
1955.
W.,
FRIED,
ANI)
JACOBSON,
cobalt
407,
SCHADE,
Chem.
142: 173, 1944.
E. D. : Thse effect
L. 0.,
of
35:
1947.
218: 595,
JACOBSON,
L. F., FRIED,
W.,
of erythsropoiesis
PLZAK,
17,
Q. I).,
J. Plsvsiol.
AND
of
14:
Anss.
,
L.,
J. Biol.
effect of cobalt.
erythropoietic
& Med.
pnol)ertmes
Biochens.
J. Biol.
ins vitro.
G. : Mechansism
Biol.
gas.
Scn1uBsnEmnI,
().,
PolcYthenssia.
S.
CARoInNE,
oxygen
L. : Magnetic
MiCHAELI5,
E.
Exper.
J.,
HEAR5ON,
histidine,
oxygersations.
8
Soc.
L.,
PLZAK,
of envthropoietins
L.
JACOBSON,
0.,
ins hypophsysectomized
E.:
GOLDWASSER,
AND
rats.
Soc.
Proc.
II.
Erythsropoiesis.
Exper.
Biol.
& Med.
Assay
92:
203,
1956.
Studies
----:
AND
on
erythropoiesis.
III.
Factors
constrolling
“
‘
pro(lmsctions.
Proc. Soc. Exper.
Biol. & Med. 94: 237, 1957.
CRAFTS,
H. C.: The effect of cobalt,
liver extracts,
amsd vitamin
B,2 n the anemia
by lsvpophysectomv
ins adunlt
fenssale
rats.
Blood
7: 863, 1952.
llontsooK,
H. A., GRAYRIEL,
A., KEIGHLEY,
C., AND WINDsoR,
E.: Polycythemic
enythro-
poietins
in
734,
‘
adult
nsonmal
rats
a Isonsprotein
to
l)lasma
extract
from
anemic
rabbits.
induiced
response
Blood
9:
1954.
J. M. AND ORTEN,
A. U.: The productions
of polycythemia
by cobalt
ins rats made
by a diet low ins proteus.
Am. J. Physiol.
139:
399, 1943.
GARDNER,
F. H.: The effect of cobaltouns
chloride
in the anemia
associated
with
chronic
rensal disease.
J. Lab.
& Cli,i. Med. 41: 56, 1953.
WINTROBE,
M. M.,
GRINSTEIN,
M.,
DUBASH,
J. J., HUMPHRYS,
S. it.,
ASHENBRUCKER,
H., AND WORTH,
W.: The
ansemia
of insfectioms.
VI. The infiuemsce
of cobalt
on anemia
associated
with
inflammation.
Blood
2: 323, 1947.
SIIEN,
S. C. AND
HUMBURGER,
F.: The ansemia
of cancer
patients
and its relation
to
metastases
to the bonse nsanrow.
J. Lab. & Clin. Med. 37: 182, 1951.
JACOBSON,
L. 0., GoLDWASSER,
E., FRIED,
W., AND PLZAK,
L.: Unpublisised
data.
GORDON,
A. S., PILIERO,
S. J., MEDICI,
P. T., SIEGEL,
C. I)., AND TANNENBAUM,
M.:
ORTEN,
anemic
‘
58
‘
20
2
Attenspts
Exper.
22
to
Biol.
JAcoBsoN,
erythropoiesis.
idenstify
& Med.
L. 0.,
site
92:
GOn.DWASSER,
Nature
598,
of l)roduction
of circuiiatinsg
“erythropoietin.”
Proc.
Soc.
1956.
E.,
179: 633,
FRIED,
1957.
W.,
AND
PLZAK,
L.:
The
role
of the
kidney
in
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
1958 13: 55-60
Studies on Erythropoiesis: V. The Effect of Cobalt on the Production of
Erythropoietin
EUGENE GOLDWASSER, LEON O. JACOBSON, WALTER FRIED and LOUIS F. PLZAK
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