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In a randomized controlled clinical trial, 14 patients requiring resection of tumors were divided in two groups: one group was anesthetized with nitrous oxide [67% N2O-33% O2 (vol/vol)] and the other with propofol. Two other groups of subjects were studied: a group of patients that was undergoing orthopedic procedures and was anesthetized with nitrous oxide [67% N2O-33% O2 (vol/vol)] and a control group (fasted for 10 hrs and no anesthesia). In patients requiring resection of tumors, the blood L-methionine concentration was significantly lower and the blood amino acid pattern was significantly affected after the administration of nitrous oxide (120-310 mins) compared with values after the induction of anesthesia and before surgery. The administration of propofol (120-240 mins) did not produce any of these changes. No patients required blood transfusion during surgery, and the patients had not previously been treated with cancer chemotherapeutic agents. The administration of nitrous oxide (60-150 mins) to patients undergoing orthopedic procedures did not affect blood L-methionine. It is concluded that the administration of nitrous oxide to cancer-bearing patients, but not to those undergoing orthopedic surgery, produced major changes in amino acid metabolism; therefore, consideration should be given to the avoidance of exposure of cancer patients to nitrous oxide.

1. Amino acid metabolism was studied in control virgin rats, lactating rats and virgin rats protein-pair-fed with the lactating rats (high-protein virgin rats). 2. Urinary excretion of nitrogen and urea was higher in lactating than in control virgin rats, and in high-protein virgin rats it was higher than in lactating rats. 3. The activities of urea-cycle enzymes (units/g) were higher in high-protein virgin than in lactating rats, except for arginase. In lactating rats the activities of carbamoyl-phosphate synthase, ornithine carbamoyltransferase and argininosuccinate synthase were lower than in control virgin rats. When the liver size is considered, the activities in lactating rats were similar to those in high-protein virgin rats, except for arginase. 4. N-Acetylglutamate content was higher in high-protein virgin rats than in the other two groups. 5. The rate of urea synthesis from precursors by isolated hepatocytes was higher in high-protein virgin rats than in the other two groups. 6. The flooding-dose method (L-[4-3H]phenylalanine) for measuring protein synthesis was used. The absolute synthesis rates of mammary gland, liver and small-intestinal mucosa were higher in lactating rats than in the other two groups, and in high-protein virgin rats than in control virgin rats 7. These results show that the increased needs for amino acids during lactation are met by hyperphagia and by a nitrogen-sparing mechanism.

Amino acid translocation was studied in the mammary gland of lactating rats and in the placenta of pregnant rats. The uptake of amino acids by the mammary gland is maximal on days 10-14 of lactation and is minimal on days 19-21. However, on day 19 maximal uptake can be restored by injection of 1) small amounts of gamma-glutamyl amino acids, 2) 5-oxoproline, and 3) an inhibitor of 5-oxoprolinase. A severe decrease in uptake of amino acids at the peak of lactation is provoked by anthglutin, an inhibitor of gamma-glutamyltranspeptidase (GGT). Simultaneous injection of 5-oxoproline blocks these effects of anthglutin. In pregnant rats, inhibition (79%) of placental GGT activity by acivicin results in a 50% decrease of placental L-[U-14C]-alanine transfer and 70-80% decrease in its incorporation into the placental and fetal proteins. Infusion of 5-oxoproline to mothers previously treated with acivicin restored the L-[U-14C]-alanine transfer. Acivicin or 5-oxoproline did not modify the transfer and metabolism of D-[U14C]glucose by the fetal placental unit. These results show that the gamma-glutamyl cycle should not be considered a mechanism for amino acid transport but rather a generator of extracellular signals, gamma-glutamyl amino acids, that are converted intracellularly to 5-oxoproline, which activates uptake and/or metabolism of amino acids.

1. Arteriovenous differences of amino acids across the lactating mammary gland were measured in normal rats and weaned for 4, 5 and 24h. 2. Uptake of amino acids by mammary glands of rats weaned for 5h or more was significantly lower than that of controls. This was not reversed by injection of prolactin. 3. By using 'unilaterally weaned' rats we showed that milk accumulation plays an important role in amino acid uptake by mammary gland. 4. gamma-Glutamyltransferase activity was significantly lower in 'weaned' glands than in 'normal' glands. This provides further support for the hypothesis of the function of the gamma-glutamyl cycle in the mammary gland in vivo.

1. Arteriovenous differences of amino acids across the lactating mammary gland have been measured in normal rats and in rats injected with serine--borate (an inhibitor of gamma-glutamyltransferase). 2. Comparison of the arteriovenous differences show that gamma-glutamyltransferase is involved in amino-acid uptake by the gland. 3. Reduced-glutathione content of isolated acini incubated with high concentrations of amino acids was lower than that of the controls. 4. High concentrations of amino acids had no effect on reduced-glutathione content of isolated acini when serine--borate was added to the incubation medium. 5. The findings provide evidence for the functioning of the gamma-glutamyl cycle in the lactating mammary gland in vivo.

Concentrations of free amino acids were measured in human milk and arterial blood from lactating women after an overnight fast or after a controlled breakfast. The concentrations of many free amino acids in milk (except L-tyrosine, L-aspartate, L-asparagine, L-glutamate and L-glutamine) were lower after an overnight fast than after breakfast. Similarly, the arterial concentrations of amino acids were lower except for L-asparagine, L-alanine, L-tyrosine and L-phenylalanine. Net uptake of amino acids by the mammary gland of the lactating rat was significantly lower after starvation for 6 or 24 h than in the fed state because the arteriovenous differences of amino acids and the blood flow were significantly lowered. Starvation produced a significant decrease of 2-amino-[1-14C]isobutyric acid uptake by isolated acini from lactating rat. These results show that short-term starvation decreases the amino acid supply and transport in mammary gland as well as the free amino acid concentration in milk.

Arteriovenous differences of amino acids across the mammary glands of lactating rats are diminished when the rats are starved for 24 h. When 24 h-starved rats were refed for 2 1/2 h, the arteriovenous differences of amino acids returned to values similar to those found in well-fed rats. In order to find a possible explanation for these rapid changes, we tested the effect of ketone bodies on amino acid uptake by the gland. At 5 min after injection of acetoacetate to fed rats, when the total concentration of ketone bodies in blood was similar to that found in starvation, the uptake of amino acids by the mammary gland was similar to that found after starvation, i.e. lower than in fed rats. However, 30 min after administration of acetoacetate, when the arterial concentration of ketone bodies had returned to values similar to those in fed rats, the arteriovenous differences of amino acids were similar to those found in fed rats. We conclude that the changes in blood ketone bodies may be responsible, at least in part, for the changes in amino acid uptake that occur in starvation and in the starvation--refeeding transition.

We showed [Biochem. J. (1981) 194, 99-102] that inhibition of gamma-glutamyl transpeptidase in vivo with serine-borate decreases amino acid uptake by mammary gland. However, doubts arose about the validity of this inhibitor in metabolic studies because it must be used in very large amounts. New inhibitors have been isolated, like anthglutin and acivicin, which are effective at low concentrations in vivo. Here, we show that treatment of lactating rats with these substances decreases the transpeptidase activity and the amino acid uptake by the gland. These results support the hypothesis that the gamma-glutamyl cycle functions as an amino acid transport system in mammary gland.

The mammary gland is a good model to study the hormonal regulation of amino acid uptake. Danazol, which decreases gonadotrophin release, causes a fall in gamma-glutamyltranspeptidase (GGT) and in amino acid uptake by the gland. Treatment of the rats with estrogens and progesterone partially reverts this effect. Treatment with gonadotrophins completely reverts it. gamma-Glutamyl-amino acids (GAA) increase the uptake of amino acids by the mammary gland in rats previously treated with bromocriptine. We suggest that GAA may act as signals to stimulate amino acid uptake and that the role of GGT may be to generate that signal.