Martín J A, Pereda J, Martínez-López I, Escrig R, Miralles V, Pallardó F V, Viña J R, Vento M, Viña J, Sastre J
Departmento de Fisiología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
Cell Mol Biol (Noisy-le-grand). 2007 Nov 30;53 Suppl:OL1010-7.
Hepatic gamma-cystathionase, a rate-limiting enzyme for the synthesis of L-cysteine from L-methionine in the trans-sulphuration pathway, exhibits significantly higher activity in the newly born infant as compared to the fetus. The aim of this work was: 1) To determine whether the increase in gamma-cystathionase activity occurring in the fetal-to-neonatal transition is due to up-regulation of its mRNA and protein, 2) To elucidate the mechanisms responsible for this increase in gamma-cystathionase activity. Our results show that expression of gamma-cystathionase at both the mRNA and protein levels was higher in newborn than in fetal liver. gamma-Cystathionase activity in fetal hepatocytes in vitro increased when incubated with tert-butyl-hydroperoxide at low concentration (0.01 mM). Hence, moderate oxidative stress would act as a signal to up-regulate gamma-cystathionase in the fetal to neonatal transition. Stress hormones, such as phenylephrine or glucagon also increased gamma-cystathionase activity in fetal hepatocytes. We also report a competitive inhibition of purified gamma-cystathionase by L-cysteine, which would help to maintain physiological low L-cysteine levels in hepatocytes. In conclusion, our results show that increased hepatic gamma-cystathionase activity in the fetal-to-neonatal transition is due to up-regulation of its gene expression mediated by stress hormones together with the physiological oxidative stress that occurs at birth.
肝脏γ-胱硫醚酶是转硫途径中从L-甲硫氨酸合成L-半胱氨酸的限速酶，与胎儿相比，其在新生儿中的活性显著更高。这项工作的目的是：1）确定胎儿向新生儿转变过程中γ-胱硫醚酶活性的增加是否归因于其mRNA和蛋白质的上调，2）阐明γ-胱硫醚酶活性增加的机制。我们的结果表明，γ-胱硫醚酶在mRNA和蛋白质水平上的表达在新生儿肝脏中均高于胎儿肝脏。当在体外与低浓度（0.01 mM）的叔丁基过氧化氢孵育时，胎儿肝细胞中的γ-胱硫醚酶活性增加。因此，适度的氧化应激将作为一种信号，在胎儿向新生儿转变过程中上调γ-胱硫醚酶。应激激素，如去氧肾上腺素或胰高血糖素也会增加胎儿肝细胞中的γ-胱硫醚酶活性。我们还报道了L-半胱氨酸对纯化的γ-胱硫醚酶具有竞争性抑制作用，这有助于维持肝细胞中生理水平的低L-半胱氨酸含量。总之，我们的结果表明，胎儿向新生儿转变过程中肝脏γ-胱硫醚酶活性的增加是由于应激激素介导的基因表达上调以及出生时发生的生理氧化应激所致。
