Oxidative stress as a signal to up-regulate gamma-cystathionase in the fetal-to-neonatal transition in rats.
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.
Martín
J A
JA
Departmento de Fisiología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
Pereda
J
J
Martínez-López
I
I
Escrig
R
R
Miralles
V
V
Pallardó
F V
FV
Viña
J R
JR
Vento
M
M
Viña
J
J
Sastre
J
J
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D000242:Cyclic AMP / Q000494:pharmacology; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D003545:Cysteine / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005333:Fetus / Q000201:enzymology; D005934:Glucagon / Q000494:pharmacology; D005978:Glutathione / Q000096:biosynthesis; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000196:embryology / Q000201:enzymology* / Q000254:growth & development; D008715:Methionine / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D012333:RNA, Messenger; D010656:Phenylephrine; D005934:Glucagon; D020122:tert-Butylhydroperoxide; D008715:Methionine; D000242:Cyclic AMP; D003542:Cystathionine gamma-Lyase; D005978:Glutathione; D003545:Cysteine