Liver gamma-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 gamma-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 gamma-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 gamma-cystathionase activity. This emphasizes the physiologic importance of the increased expression and activity of liver gamma-cystathionase during lactation.
Conflict of interest: COI declared -see note COI notes: PG reports speaker honoraria from Novartis and Abbvie and fees from Novartis and Abbvie for participation on advisory boards. AMV has personal fees as advisory bord and speaker fee from AOP Orphan Pharmaceuticals and Novartis. AR has personal fees as advisory board from Astellas, Amgen, Celgene BMS, Gilead, Italfarmaco, Novartis, Omeros, Roche, and Sanofi. TB declares personal fees as advisory bord from AOP Orphan Pharmaceuticals, Italfarmaco, and Novartis, outside the submitted work. The remaining authors declare no competing financial interests. Preprint server: No;Author contributions and disclosures: PG interpreted the data, and wrote the brief report. TB conceived and designed the study, supervised the analysis and critically revised the brief report. AG and AC contributed to dataset preparation, planned and performed statistical analyses. AM directed the project. AMV interpreted the data and critically revised the brief report.
To study the fate of L-cysteine and amino acid homeostasis in liver after the inhibition of the transsulfuration pathway, rats were treated with propargylglycine (PPG). At 4 h after the administration of PPG, liver cystathionase (EC 4.4.1.1) activity was undetectable, L-cystathionine levels were significantly higher, L-cysteine was unchanged and GSH concentration was significantly lower than values found in livers from control rats injected intraperitoneally with 0.15 M-NaCl. The hepatic levels of amino acids that are intermediates of the urea cycle, L-ornithine, L-citrulline and L-arginine and blood urea were significantly greater. Urea excretion was also higher in PPG-treated rats when compared with control rats. These data suggest a stimulation of ureagenesis in PPG-treated rats. The inhibition of y-cystathionase was reflected in the blood levels of amino acids, because the Lmethionine : L-cyst(e)ine ratio was significantly higher in PPG-treated rats than in control rats; blood concentration of cystathionine was also greater. Histological examination of liver and kidney showed no changes in PPG-treated rats when compared with controls. The administration of Nacetylcysteine (NAC) to PPG-treated rats reversed the changes in blood urea and in liver GSH. These data suggest that when liver L-cysteine production was impaired by the blockage of the transsulfuration pathway, the concentration of this amino acid was maintained mainly by an increase in protein degradation and by a depletion in GSH concentration that may spare L-cysteine. Liver: Cysteine: Propargylglycine: CystathionaseThe maintenance of intracellular L-cysteine concentration in liver is achieved by several mechanisms: (1) the trans-sulfuration pathway, (2) the uptake from plasma, (3) proteolysis, (4) the rate of L-cysteine incorporation into GSH and (5) the conversion to taurine. The availability of L-cysteine is the rate-limiting step for the synthesis of GSH by mammalian cells (Tateishi et al. 1974;Beutler, 1989); therefore, the capacity of tissues, mainly the liver, to synthesize L-cysteine from L-methionine is important to cell homeostasis (Rose & Wixom, 1955). It has been estimated that 5040% of the dietary L-methionine requirements can be dispensed with if the diet is supplemented with L-cysteine, and for this reason the latter has been called a conditionally indispensable amino acid (Laidlaw & Kopple, 1987) in those situations in which cystathionase activity is low.The daily turnover of L-methionine which includes the incorporation into and release from protein and the conversion of methionine to homocysteine and its remethylation, is approximately double the dietary intake (Nunn, 1987), therefore the recycling of Lmethionine from homocysteine is important (Finkelstein, 1990). However, homocysteine is available at https://www.cambridge.org/core/terms. https://doi
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