Vol.
167,
March
No.
30,
3, 1990
A
AND
BIOPHYSICAL
SMALLER
INITIAL LETHAL
Costell,
Instituto
de
DOSE DOSES
PROTECTS OF AMMDNIUM
Jose-Enrique
Investigaciones
Valencia.
6,
AGAINST ACETATE
and
Citologicas
Centro
February
MICE
O’Connor
Asociado
COMMUNICATIONS
CSIC.
la
1263-1270
SEUERAL
Santiago
de
de1
46610-Ualencia,
Received
RESEARCH
Pages
Mercedes
de
BIOCHEMICAL
1990
Grisolia
Caja
fknadeo
de
de
Ahorros
Saboya,4.
Spain
1990
of urea in the liver is the main mechanism ABSTRACT .The synthesis for the el iminat ion of excess ammonia. Rapid stimulation of the synthesis of urea Ce .g. by administration of carbamyl glutamate, the analog of the physiological actiuator of carbamyl phosphate synthetase I) protects animals given lethal doses of ammonia. Since ammonia enhances the activity of the urea cycle, we tested and show administration of small doses of ammon i urn acetate here that supresses the mortality induced by a series of repeated LO100 of ammon i urn acetate separated by one hour, when the first LO160 is injected i .p. starting from 30 min to 5 hours after the initial acetate. Under these condi t ions, the smal ler dose of ammon i urn levels of ammonia in blood are elevated more than ten times, but in ammonemia spi te of the greater amount of ammonia administered, the is much lower than in mice dying after a single LDlOO. The enhanced obserued is correlated with an increase in the synthesis of urea N-acetyl glutamate. These findings intrami tochondrial content of cycle, are of interest as far as the short-term regulation of urea the mechanism of ammonia toxicity and have clinical implications. 0 1990
Academic
Ammonia main
2~s~.
Inc.
is
a
factor in
narrow
limits
product
hepat
animals mainly
ic
by
production
enzymes
(3)
by
considered
cl).
kept
under
operat
t he
ion
most
ei
urea,
ther
accumulation
by
of
inborn
metabolic
as
The
leuels
conditions
of
the
hyperammonemias of
or
currently
encephalopaty
are
life-threatening
impaired
regulated
in
ureotelic
Conversely,
The
neurotoxic
implied
ammonia
inhibitors
highly
C4)
urea
cycle
(2).
from in
or
of within
result errors
a
urea
an cycle
pharmacological
(5).
synthesis
of at
urea several
is
a points.
uer
Y
efficient
Short-term
but activation
complex
mechanism of
0006-291X/90 263
urea
$1.50
Copyright 0 1990 by Academic Press, Inc. All rights of reproduction in any fotm reserved.
Vol.
167,
No.
BIOCHEMICAL
3, 1990
synthesis
is
usual
intramitochondrial
We
activator
have
shown
against
the
carni prevents
the
Since
the
results
an
of
We
of
of
r-easoned
to
Od
mice
and
ammon
i urn
sal
glutamate
doses,
al so 1 iver
synthesis
could thus
t s
in the
Ia
rats
acetate.
priming
lethal
protection
ammonium
ammon
167,
March
No.
30,
3, 1990
A
AND
BIOPHYSICAL
SMALLER
INITIAL LETHAL
Costell,
Instituto
de
DOSE DOSES
PROTECTS OF AMMDNIUM
Jose-Enrique
Investigaciones
Valencia.
6,
AGAINST ACETATE
and
Citologicas
Centro
February
MICE
O’Connor
Asociado
COMMUNICATIONS
CSIC.
la
1263-1270
SEUERAL
Santiago
de
de1
46610-Ualencia,
Received
RESEARCH
Pages
Mercedes
de
BIOCHEMICAL
1990
Grisolia
Caja
fknadeo
de
de
Ahorros
Saboya,4.
Spain
1990
of urea in the liver is the main mechanism ABSTRACT .The synthesis for the el iminat ion of excess ammonia. Rapid stimulation of the synthesis of urea Ce .g. by administration of carbamyl glutamate, the analog of the physiological actiuator of carbamyl phosphate synthetase I) protects animals given lethal doses of ammonia. Since ammonia enhances the activity of the urea cycle, we tested and show administration of small doses of ammon i urn acetate here that supresses the mortality induced by a series of repeated LO100 of ammon i urn acetate separated by one hour, when the first LO160 is injected i .p. starting from 30 min to 5 hours after the initial acetate. Under these condi t ions, the smal ler dose of ammon i urn levels of ammonia in blood are elevated more than ten times, but in ammonemia spi te of the greater amount of ammonia administered, the is much lower than in mice dying after a single LDlOO. The enhanced obserued is correlated with an increase in the synthesis of urea N-acetyl glutamate. These findings intrami tochondrial content of cycle, are of interest as far as the short-term regulation of urea the mechanism of ammonia toxicity and have clinical implications. 0 1990
Academic
Ammonia main
2~s~.
Inc.
is
a
factor in
narrow
limits
product
hepat
animals mainly
ic
by
production
enzymes
(3)
by
considered
cl).
kept
under
operat
t he
ion
most
ei
urea,
ther
accumulation
by
of
inborn
metabolic
as
The
leuels
conditions
of
the
hyperammonemias of
or
currently
encephalopaty
are
life-threatening
impaired
regulated
in
ureotelic
Conversely,
The
neurotoxic
implied
ammonia
inhibitors
highly
C4)
urea
cycle
(2).
from in
or
of within
result errors
a
urea
an cycle
pharmacological
(5).
synthesis
of at
urea several
is
a points.
uer
Y
efficient
Short-term
but activation
complex
mechanism of
0006-291X/90 263
urea
$1.50
Copyright 0 1990 by Academic Press, Inc. All rights of reproduction in any fotm reserved.
Vol.
167,
No.
BIOCHEMICAL
3, 1990
synthesis
is
usual
intramitochondrial
We
activator
have
shown
against
the
carni prevents
the
Since
the
results
an
of
We
of
of
r-easoned
to
Od
mice
and
ammon
i urn
sal
glutamate
doses,
al so 1 iver
synthesis
could thus
t s
in the
Ia
rats
acetate.
priming
lethal
protection
ammonium
ammon
