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-Cystathionase Is Required for the Maintenance of Lactation in Rats1
Departamento de Bioquímica y Biología Molecular, Facultades de Medicina-Farmacia, Universitat de Valencia, Valencia, Spain
2To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-cystathionase activity increases in rats during lactation;
its inhibition due to propargylglycine is followed by a significant
decrease in lactation. This is reversible by
N-acetylcysteine administration. To study the role of
liver -cystathionase and the intertissue flux of glutathione during
lactation, we used lactating and virgin rats fed liquid diets. Virgin
rats were divided into two groups as follows: one group was fed daily a
diet containing the same amount of protein that was consumed the
previous day by lactating rats (high protein diet–fed rats); the other
virgin group was fed the normal liquid diet (control). The expression
and activity of liver -cystathionase were significantly greater in
lactating rats and in high protein diet–fed virgin rats compared with
control rats. The total glutathione [reduced glutathione (GSH) +
oxidized glutathione (GSSG)] released per gram of liver did not differ
in lactating rats or in high protein diet–fed rats, but it was
significantly higher in these two groups than in control virgin rats.
Liver size and the GSH + GSSG released by total liver were
significantly higher in lactating rats than in high protein diet–fed
virgin rats, and this difference was similar to the amount of
glutathione taken up by the mammary gland (454.2 ± 36.0
nmol/min). The uptake of total glutathione by the lactating mammary
gland was much higher than the uptakes of free L-cysteine
and L-cystine, which were negligible. These data suggest
that the intertissue flux of glutathione is an important mechanism of
L-cysteine delivery to the lactating mammary gland,
which lacks -cystathionase activity. This emphasizes the physiologic
importance of the increased expression and activity of liver
-cystathionase during lactation.
KEY WORDS: • L-cysteine • glutathione • lactating mammary gland • L-cystathionine • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Rao et al. 1990
,
Stipanuk 1986
). L-Methionine metabolism has
two branched sites. The first branch point is the utilization of
L-methionine for either protein synthesis or the synthesis
of S-adenosylmethionine, which plays a pivotal role as a
methyl donor in a great number of biochemical events (Chiang et al. 1996
). The second is the distribution of
L-homocysteine between the reaction of the transsulfuration
pathway, which is catalyzed by cystathionine-ß-synthase, and the
remethylation with the use of 5-methyl-H4-folate
as a methyl donor. This is catalyzed by L-methionine
synthase. There is another alternative for L-homocysteine
remethylation. This is the betaine pathway, which is induced in rat
liver when the L-methionine synthase pathway is blocked by
N2O (Nunn 1987
).
The transsulfuration pathway is incomplete in heart, testes, lung,
adrenal, spleen, mammary gland and brain because they lack
-cystathionase; therefore, L-cysteine may be considered
an essential substrate for these tissues. The supply of this amino acid
to those tissues lacking the transsulfuration pathway can be achieved
by delivery of L-cysteine, L-cystine and GSH if
-glutamyltranspeptidase (GGT) is expressed in the tissue. This is
possible because there is an interorgan flow of GSH from liver to those
tissues with high GGT activity (Anderson et al. 1980
,
Meister and Anderson 1983
).
Lactation is characterized by physiologic adaptations and changes in
metabolism of different tissues to ensure a sufficient supply of
nutrients to the mammary gland. Among the physiologic changes, the most
prominent are hyperphagia, liver hypertrophy and increased blood flow
to the mammary gland (Wade and Schneider 1992
,
Williamson et al. 1995
). Because increased food intake
during lactation means an increased protein intake, we used the
following three different groups of rats: rats at their peak of
lactation, virgin rats and virgin rats that had the same protein intake
as lactating rats. The last-mentioned group was introduced to
dissociate the effects of lactation from those of protein intake. By
using this experimental approach, it was shown that the increased needs
for amino acids during lactation are met by hyperphagia, a
nitrogen-sparing mechanism and a specific redistribution of amino
acids to the mammary gland (Barber et al. 1990
,
García de la Asunción et al. 1994
).
Because lactating rats have an increased expression of liver
-cystathionase compared with virgin rats (Awata et al. 1993
) and the -cystathionase activity in the lactating
mammary gland is undetectable, it was of interest to elucidate how the
L-cysteine needs are met during lactation. This is of
interest because the expression of -cystathionase in premature
neonates is delayed, and the amount of L-cysteine in milk
is rate limiting for growth and development. The aims of this work were
to study the effect of liver -cystathionase inhibition on lactation,
the reason for the high expression and activity of liver
-cystathionase during lactation and how the delivery of
L-cysteine to the mammary gland during lactation is
achieved.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Female Wistar rats were cared for and handled in conformance with the
NIH guidelines (NRC 1985
) and the Guiding Principles for
Research Involving Animals and Humans approved by the Council of The
American Physiological Society. All rats were maintained on a 12-h
light:dark cycle in a room with controlled temperature (22°C). Rats
used were either virgin or in their first lactation. The lactating rats
had between eight and ten pups and were used at the peak of lactation,
d 11–14.
Experiment 1.
A group of 8 virgin and 28 lactating rats fed a standard diet (Panlab,
Barcelona, Spain) were used in this experiment. The composition of this
diet was as follows (g/kg): carbohydrates, 590; lipids, 30; and
protein, 160. Eight virgin rats were used to measure the
-cystathionase activity. The 28 lactating rats were divided as
follows. One group of eight lactating rats was used as control. Another
group of eight lactating rats was injected daily with propargylglycine
(PPG) (50 mg/kg, intraperitoneally) for 3 d (lactating + PPG). A
group of five lactating rats was injected every 6 h with
N-acetyl-L-cysteine (NAC; 50 mg/kg) over a
period of 3 d (lactating + NAC). Another group of seven
PPG-treated lactating rats was injected every 6 h with NAC (80
mg/kg, intraperitoneally) during the 3-d period (lactating + PPG +
NAC).
Experiment 2.
Thirty lactating and 36 virgin rats (20 control and 16 protein
pair-fed with the lactating rats) were used. The rats were fed the
solid standard diet described above until they reached the age of 2-3
mo. They were then fed a liquid diet (Barber et al. 1990
, García de la Asunción 1994
)
from special glass containers to which they were given free access.
Water was available in separate glass containers. The liquid diet was
offered to the lactating rats for 2 wk, starting on d 1 of lactation.
The two groups of virgin rats (control virgin and protein pair-fed
with the lactating rats) also received the diet for 2 wk. No
intubations were performed. The volume of liquid diet consumed by each
rat was recorded every morning. Virgin rats drank 85 mL of this liquid
diet ad libitum. Because lactating rats increased their intake as
lactation progressed, it was necessary to raise the dietary protein
concentration gradually while maintaining the same amount of other
macro- and micronutrients and adding water to the same final
volume;thus the protein pair-fed virgin rats would still be
consuming the same amount of protein that was consumed the previous day
by the lactating rats. The virgin rats pair-fed to the lactating
rats on the basis of protein were introduced to dissociate the effects
of hormonal changes of lactation from those of protein intake;
lactating rats have hyperphagia, and the level of protein intake
affects the metabolism of protein and amino acids. The liquid diet
consumed by the lactating and control virgin rats was formulated
according to the ASNS recommendations. The energy distribution of the
diet was 22% protein, 12% lipid and 66% carbohydrate. The energy
content of this diet was 4184 kJ/L. The diet composition was as follows
(g/L): vitamin-free casein, 54.5; DL-methionine, 0.8;
corn oil, 3.4; olive oil, 10.1; sucrose, 131.2; dextrin, 39.4; vitamin
mix, 2.6 (AIN 1977
and 1980
); mineral mix 9.2
(AIN, 1977
); choline chloride, 0.4; xanthan gum, 2.0;
and cellulose powder, 10.0; distilled deionized water to final volume.
The vitamin and mineral mixes were changed to meet the new
recommendations (Reeves et al. 1993
) in 12 lactating and
14 virgin rats. All diets were prepared daily.
Sampling procedures, amino acid and GSH determinations.
The rats were sampled 3–4 h after the beginning of the light cycle.
They were anesthetized intraperitoneally with sodium pentobarbital (60
mg/kg body wt) and maintained at 37°C with a homeothermic blanket.
Blood was collected in heparinized syringes from the
pudic-epigastric, hepatic and portal veins and then from the aorta.
When liver was removed, a piece was immediately used for
-cystathionase activity. The rest of liver was cut free and clamped
between tongs cooled in liquid N2; the samples were kept in
liquid N2 until they were used.
Plasma amino acids were measured on a amino acid analyzer (model 3201,
LKB, Cambridge, UK). L-Cysteine was determined by a
spectrophotometric method (Gaitonde 1967
). For the
GSH/GSSG ratio in liver, GSH was measured by using the
GSH-S-transferase assay (Brigelius et al. 1983
); oxidized glutathione (GSSG) was assayed by the HPLC
method with UV-V detection, which measures GSSG in the presence of
a large excess of GSH (Asensi et al. 1994
). For the
intertissue flux of total glutathione, GSH equivalents (GSH + 2GSSG)
were measured and expressed as µmol/L of plasma
(Fariss and Reed 1987
).
RNA isolation and amplification.
Total RNA isolation was performed with the use of a High Pure Isolation Kit (Boehringer Mannheim, Germany), which is based on the specific binding of nucleic acids to the surface of glass fibers after the addition of a chaotropic salt. The purified total RNA from liver was converted to single-stranded cDNA for subsequent amplification using a one-step reverse transcriptase-polymerase chain reaction (RT-PCR) (Titan one tube RT-PCR system, Boehringer Mannheim).
Two synthetic oligonucleotide primers derived from the nucleotide
sequence of -cystathionase (5'-ATCACACCACAGACCAAGCT-3' and
5'-AGGCTCTCAGCCAGAGCAAA-3') were used for PCR amplification.
The mRNA for ribosomal protein S26 and mRNA for glyceraldehyde
3-phosphate dehydrogenase (GADPH) were used as standards for RNA
quantification. The PCR products were analyzed by agarose gel
electrophoresis. To check the amplification specificity, the PCR
products corresponding to -cystathionase were digested with Eco RI,
which produces two fragments of 282 and 302 bp.
To quantify the -cystathionase expression, the ratio of
-cystathionase to GAPDH was obtained by densitometric analysis of
the negative corresponding to the film of the RT-PCR products
checked by electrophoresis on agarose gels (see Fig. 1
). The mean value for control virgin rats was considered to be
100%.
|
-Cystathionase activity.
The activity of this enzyme (EC 4.4.1.1)in liver was studied by
determining the rate of L-cysteine synthesis from
cystathionine (Heinonen 1973
).
Milk production.
The following equation relating dam milk yield to pup weight and weight
gain was used to estimate milk production: Yield = 0.0322 +
0.0667(weight) + 0.877(gain), where yield is daily yield per pup per
day, weight is pup weight (g) and gain is pup daily weight gain (g/d)
(Sampson and Jansen 1984
).
Milk collection.
Milk was collected as described (Lake 1983
). Eight
lactating rats fed the liquid diet were used exclusively for this
purpose. Rats were sedated with 0.5 mL/kg of a 10:1 ketamine
hydrochloride (100g/L) and chlorpromazine (25g/L). Oxytocin (0.5
IU in 0.5 mL of 9 g/L sterile saline) was given
intraperitoneally immediately before milking.
Statistics.
In Experiment 1, a two-way ANOVA was performed; in Experiment 2, a
one-way ANOVA was performed. The homogeneity of the variances was
analyzed by the Levene test; in those cases in which the variances were
unequal, the data were adequately transformed before ANOVA. The null
hypothesis was accepted for all of the values of these sets in which
the F-value was nonsignificant at P
> 0.05. The data for which the F-value was
significant were examined by Tukey's test at P < 0.05. Wilcoxon's test was used to compare -cystathionase activity
in Figure 1
. Values in the text are means ± SEM.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-Cystathionase activity and L-cystathionine,
L-cysteine and GSH concentrations in liver from lactating
rats.
The -cystathionase activity in lactating mammary glands was
undetectable; in liver, it was significantly higher in lactating rats
than in the virgin rats (lactating: 0.38 ± 0.02
µmol/(min · g), virgin: 0.23 ± 0.01
µmol/(min · g), P < 0.05). When
PPG, which is an irreversible inhibitor of -cystathionase, was
injected into lactating rats, liver -cystathionase activity was
undetectable, and L-cystathionine concentration was two
orders of magnitude greater than in control lactating rats (Table 1). L-Cysteine did not differ and GSH concentration was
significantly lower than in the control lactating rats. The
administration of NAC to control lactating rats and PPG-treated
lactating rats increased the concentrations of GSH and
L-cysteine (P < 0.05).
|
-cystathionase decreases lactation and is
reversed by NAC.
Inhibition of liver -cystathionase with PPG over a period of 72 h produced an inhibition of lactation that was reflected in lower milk
production compared with control lactating rats (Table 2). This difference was significant 24 h after injection of
PPG. NAC prevented this decrease in milk production found in
PPG-lactating rats. The NAC injection to control lactating rats did
not modify milk production. The arteriovenous differences of
L-threonine, L-serine,
L-asparagine, L-glutamate,
L-glutamine, glycine, L-alanine,
L-isoleucine, L-leucine,
L-phenylalanine and L-arginine were
significantly lower in PPG-treated rats compared with controls
(Table 3). Administration of NAC to PPG-treated rats resulted in
arteriovenous differences of amino acids that generally did not differ
from control values. The arteriovenous difference of total GSH in
PPG-treated rats was 5% of the value found in the lactating
control rats (results not shown).
|
|
Daily intake of liquid diet in control virgin rats, lactating rats,
and high protein diet–fed virgin rats.
The energy intake of the lactating group was significantly higher than
the intakes of the other two groups because lactation is associated
with hyperphagia (Table 4). Protein intake did not differ in the lactating rats and high
protein diet–fed virgin rats, and it was higher in both than in the
virgin control group.
|
-cystathionase of control
virgin rats, lactating rats and high protein diet–fed rats.
The activity of hepatic -cystathionase in lactating and high protein
diet–fed virgin rats did not differ and was significantly higher than
in controls (Fig. 1)
. Liver GSH/GSSG and L-cystine and
L-cysteine concentrations did not differ among the three
groups (results not shown).
The ratio between cystathionase and GAPDH for lactating and high
protein diet–fed virgin rats was 242 ± 66 (n = 3) and 269 ± 93 (n = 3), respectively, compared
with 100 in controls (Fig. 1)
.
Total glutathione released by liver and uptake of total
glutathione, L-cysteine and L-cystine by the
lactating mammary gland.
The hepatic release of total glutathione in lactating and protein
pair-fed virgin rats was significantly higher than in the controls
(Table 5). No difference was observed between the lactating and the protein
pair-fed virgin rats when total glutathione was express per gram of
liver. However, due to the liver hypertrophy of the lactating rats, the
total glutathione released by liver in lactating rats was significantly
higher than in the protein pair-fed rats. This difference (577
nmol/min) was similar to the amount of glutathione taken up by the
lactating mammary gland (Table 5)
.
|
) and in control rats fed a standard diet (Table 3)
.
L-Cysteine, L-alanine and L-lysine
are the most abundant amino acids in milk; L-cysteine is
the best donor of sulfur to the neonate because its concentration is
much higher than those of GSH and L-cystine in milk. The
milk concentrations of L-threonine, taurine,
L-serine and L-arginine are also high compared
with other amino acids.
|
|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), increased blood flow to the mammary gland
(Williamson et al. 1995
), redistribution from different
tissues to the mammary gland (Tedstone et al. 1990
) and
a nitrogen-sparing mechanism (Barber et al. 1990
,
García de la Asunción et al. 1994
).
However, in spite of these homeorhetic mechanisms to ensure an adequate
supply of free amino acids to the lactating mammary gland, there is in
vitro evidence showing that GSH utilization is mediated by GGT and that
this tripeptide is an important donor of L-cysteine. With
the use of bovine mammary acini, it was shown that the label from
35S-GSH is incorporated into the
acid-precipitable proteins when substrates are provided for protein
synthesis. Similar results were obtained with GSSG as a substrate; the
inclusion of a GGT inhibitor decreased the incorporation of
35S into protein (Baumrucker et al. 1981
). The lactating mammary gland can also use other peptides
as a source of amino acids. This is the case for some
methionine-containing di- and tripeptides, which promote a higher
incorporation of 3H-leucine into secreted
proteins than free L-methionine in mammary tissue explants
from d 10–11 lactating CD-1 mice (Wang et al. 1996
).
There is a flow of total glutathione from tissues with low GGT activity
to plasma and from plasma to those tissues with high GGT activity. The
major organs involved in this intertissue flux of GSH are the liver,
which has low GGT activity, and the kidney, pancreas and the lactating
mammary gland, which are tissues with high GGT activity; thus, the
increased production and release of GSH by the liver is important
during lactation. The amount and activity of liver -cystathionase
increase significantly during lactation (Awata et al. 1993
). The importance of this enzyme for the maintenance of
lactation is clear because propargylglycine injection produces an
inhibition of -cystathionase and a decrease of liver GSH, as
previously described for virgin rats injected with PPG (Triguero et al. 1997
).This is followed by a decrease in milk production
and in the arteriovenous difference of amino acids and GSH, but this is
reversed by the administration of
N-acetyl-L-cysteine, which yields
L-cysteine, the product of the -cystathionase reaction
and a very good precursor of GSH.
The increased protein intake due to the hyperphagia during lactation
explains the high activity of this enzyme. However, the release of
total glutathione (GSH + GSSG) by total liver was significantly higher
in the lactating rats than in the protein pair-fed virgin rats;
this was due to the liver hypertrophy. The signals responsible for the
high release of total glutathione by liver of lactating rats are the
increase in protein intake, which modulates the expression and activity
of hepatic -cystathionase, and the liver hypertrophy, which is
unrelated to protein intake and is due to physiologic changes of
lactation (Barber et al. 1990
).
The data from rats fed a liquid diet, the arteriovenous differences of
L-cysteine and L-cystine (Table 6)
, together
with the blood flow to the mammary gland and the total weight of the
mammary gland (Viña et al. 1987
), allow us to
estimate that the total uptake of L-cysteine and
L-cystine is 21 and 52 nmol/(min·gland), respectively.
These values are lower than the uptake of total glutathione (GSH +
GSSG) by the mammary gland, which is 454 nmol/(min · gland) (Table 5)
. Thus, GSH is the most important source of milk
L-cysteine because it can be used by the mammary gland as a
result of the activity of GGT, an enzyme that is present in high levels
in the lactating mammary gland (Baumrucker et al. 1981
,
Viña et al. 1981
). This enzyme is also involved in
the regulation of amino acid uptake by different tissues, including the
lactating mammary gland and the blood-brain barrier (Lee et al. 1996
, Viña et al. 1989
).
The supply of L-cysteine as a component of milk protein and
as a nonprotein compound is important to neonates, especially the
premature, because -cystathionase is not fully expressed
(Pallardó et al. 1991
, Sturman et al. 1970
, Viña et al. 1995
). Therefore,
L-cysteine can be considered an essential amino acid in the
first days of life. This emphasizes the physiologic importance of this
intertissue flux of GSH found in the lactating mother, because it
allows a delivery of L-cysteine to the mammary gland, thus
ensuring that the neonate receives the amount of this amino acid
required for normal growth and development through the milk.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
3 Abbreviations used: GADPH, glyceraldehyde
3-phosphate dehydrogenase; GGT, -glutamyltranspeptidase; GSH,
reduced glutathione; GSSG oxidized glutathione; NAC,
N-acetyl-L-cysteine; PPG propargylglycine;
RT-PCR, reverse transcriptase-polymerase chain reaction.
Manuscript received August 19, 1998. Initial review completed October 3, 1998. Revision accepted January 21, 1999.
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