Liver intracellular L-cysteine concentration is maintained after inhibition of the trans-sulfuration pathway by propargylglycine in rats

Abstract

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

Cystathionine γ-Lyase-deficient Mice Require Dietary Cysteine to Protect against Acute Lethal Myopathy and Oxidative Injury

“…Several lines of evidence indicate that cystathioninuria/cystathioninemia is caused by a deficiency of CTH; for example, 1) CTH activity was markedly reduced in the liver extracts or the cultured lymphoid cell lines of patients with cystathioninuria (38, 39); 2) systemic administration of propargylglycine (an irreversible CTH inhibitor) to rats induced cystathioninemia (40,41); and 3) multiple Cth mutations were found in unrelated probands with cystathioninuria (42,43). Here, we provide the first genetic evidence that the deletion of CTH alone causes cystathioninuria and cystathioninemia.…”

Sulfur as a Signaling Nutrient Through Hydrogen Sulfide

“…Cysteine is a limiting substrate for fueling the synthesis of sulfur metabolites present at high intracellular concentrations, for example, GSH [up to 10 mM (164)] and taurine [ranging from 10 to 50 mM (114)]. The transsulfuration pathway is a significant source of cysteine in mammals, and its inhibition results in an ~50% decrease in GSH levels in cultured cells (26, 88, 183, 296) and in tissues (44, 59, 282). GSH is synthesized from cysteine in two ATP-dependent steps (164).…”

Production and Actions of Hydrogen Sulfide, a Novel Gaseous Bioactive Substance, in the Kidneys

“…It has been shown that PPG at a dose of 50 mg/kg does not cause histological abnormalities in the kidneys (Triguero et al, 1997).…”