Abstract
Our investigation showed that hepatocytes isolated from cysteine dioxygenase knockout mice (Cdo1−/−) had lower levels of hypotaurine and taurine than Cdo1 +/+ hepatocytes. Interestingly, hypotaurine accumulates in cultured wild-type hepatocytes. dl-propargylglycine (PPG, inhibitor of cystathionine γ-lyase and H2S production) dramatically decreased both taurine and hypotaurine levels in wild-type hepatocytes compared to untreated cells. Addition of 2 mM PPG resulted in the decrease of the intracellular taurine levels: from 10.25 ± 5.00 observed in control, to 2.53 ± 0.68 nmol/mg protein (24 h of culture) and from 17.06 ± 9.40 to 2.43 ± 0.26 nmol/mg protein (control vs. PPG; 48 h). Addition of PPG reduced also intracellular hypotaurine levels: from 7.46 ± 3.55 to 0.31 ± 0.12 nmol/mg protein (control vs. PPG; 24 h) and from 4.54 ± 3.20 to 0.42 ± 0.11 nmol/mg protein (control vs. PPG; 48 h). The similar effects of PPG on hypotaurine and taurine levels were observed in culture medium. PPG blocked hypotaurine/taurine synthesis in wild-type hepatocytes, suggesting that it strongly inhibits cysteinesulfinate decarboxylase (pyridoxal 5′-phosphate-dependent enzyme) as well as cystathionine γ-lyase. In the presence of PPG, intracellular and medium cystathionine levels for both wild-type and Cdo1 −/− cells were increased. Addition of homocysteine or methionine resulted in higher intracellular concentrations of homocysteine, which is a cosubstrate for cystathionine β-synthase (CBS). It seems that PPG increases CBS-mediated desulfhydration by enhancing homocysteine levels in hepatocytes. There were no overall effects of PPG or genotype on intracellular or medium glutathione levels.
Highlights
In mammals, cysteine is catabolized by several nonoxidative cysteinesulfinate-independent desulfuration pathways as well as by oxidative cysteinesulfinate-dependent pathways or it may be used for protein and glutathione synthesis (Fig. 1)
We have investigated the effect of propargylglycine (PPG; inhibitor of gamma-cystathionase) on hepatic hypotaurine and taurine synthesis and the levels of cystathionine, total unbound homocysteine, and glutathione in hepatocytes isolated from wild-type and Cdo1 knockout male mice
Intracellular cystathionine levels in wild-type hepatocytes cultured in the presence of PPG were 34-times those of the corresponding non-PPG values, whereas those for Cdo1−/− hepatocytes cultured in the presence of PPG were 14-times those of the corresponding non-PPG values, with the lower fold increases in Cdo1−/− cells being related to their higher basal levels of cystathionine
Summary
Cysteine is catabolized by several nonoxidative cysteinesulfinate-independent desulfuration pathways as well as by oxidative cysteinesulfinate-dependent pathways or it may be used for protein and glutathione synthesis (Fig. 1). Cysteine is catabolized by several desulfuration reactions that release sulfur in a reduced oxidation state, generating sulfane sulfur or hydrogen sulfide (H2S), which can be further oxidized to sulfate. The main pathway of taurine synthesis in mammals involves the oxidation of l-cysteine by the cysteine dioxygenase (CDO) to produce cysteine sulfinic acid. This acid is decarboxylated to hypotaurine by the cysteine sulfinic acid decarboxylase, which is oxidized to Methionine
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