Aims-To determine the level of oxidative stress and cell damage as a result of exposure to O 2 at birth. Methods-Using glutathione S transferase (GST) as an indicator of oxidative stress, GST activity in cord blood was compared with that in samples taken three hours after birth. Twenty four prematurely born infants and eight full term infants were studied. To test whether stronger eVects occur under less favourable conditions, the neonates were divided in three groups: healthy premature; sick premature; and healthy full term infants. Results-GST activity three hours after birth was significantly decreased compared with that at birth in all three groups tested. There were no significant diVerences in the magnitude of this eVect among the three groups. Conclusions-These results indicate that a sudden increase in oxygenation exposes the neonate to oxidative stress. Measurement of GST activity might be useful for the evaluation of protective treatment in trials considering antioxidant strategies. (Arch Dis Child Fetal Neonatal Ed 1999;81:F130-F133) Keywords: glutathione S transferase; oxidative stress; birth; prematurity Birth exposes the neonate to a higher pO 2 than experienced in utero. The sudden increase in alveolar oxygen concentration and arterial pO 2 after delivery increases the formation of reactive oxygen species in the lung 1 and other organs. Free oxygen radicals seem to have a role in mediating tissue damage in hyperoxia and reperfusion after ischaemia, 2 in inflammatory processes, 3 and after circulatory shock. 4 When the antioxidant capacity of the neonate is inadequate to oppose the increased formation of reactive oxygen species after birth, this may result in an oxidative stress and cell damage. The main glutathione S transferase (GST) isoenzyme in human erythrocytes, with activity towards the common substrate 1-chloro-2,4-dinitro-benzene (CNDB), belongs to the -class. 5 Rat GST of this class can be deactivated by oxidation of a cysteine (47-Cys) near the active centre. 6 We have already shown that inhibition of erythrocyte GST from human adults can be used in vitro to indicate oxidative stress after treatment with hydroxylamines, 7 in vivo after intensive exercise, 8 and in coal workers' pneumoconiosis.9 GST activity with the same catalytic properties as the enzyme form in adult erythrocytes, is present after 12 weeks of gestation in fetal erythrocytes. 10 In contrast to catalase and selenium dependent glutathione peroxidase, GST activity in erythrocytes is inversely related to increasing gestational age, and adult values are lower than any of the neonatal values. 11On the assumption that the glutathione S transferase enzyme in neonatal red blood cells has the same properties as those of adult erythrocytes, it is to be expected that this enzyme is also vulnerable to oxidative stress. When strong oxidative stress conditions occur at birth, the activity of such a vulnerable enzyme could decrease. The extent of that decrease could be even greater under more extreme oxidative stresses.To t...
1 The administration of S-warfarin (1 mg kg-' i.v.) to rats that were pre-loaded 48 h before with tracer doses (6 yg) of "4C-labelled R-or S-warfarin caused the plasma levels of these compounds to increase. This is due to the substitution of the microsomal (vitamin K 2,3-epoxide (KO) reductase) bound R-or S-["4C]-warfarin by the unlabelled 4-hydroxycoumarin administered. The rate of reappearance was 3-4 fold higher for R-than for S-warfarin; t1,2 of release: 1.2 + 0.04 and 3.7 + 0.6 h, respectively.2 Liver microsomes prepared from rats pretreated with R-or S-[14C]-warfarin, released these compounds only in the presence of dithiothreitol (DTT; 10mM). The rate of release was higher for R-than for S-warfarin-treated microsomes. 3 Liver microsomes treated in vitro with R-or S-acenocoumarol could be reactivated by DTT (O1mM). Reactivation was higher for the R-than for the S-acenocoumarol-treated microsomes.4 The microsomal vitamin KO reductase activity under 'normal' assay conditions ([DTT] = 2 mM) was as sensitive for R-as for S-4-hydroxycoumarins. At elevated DTT concentrations (= 42 mM) the rate of vitamin KO conversion was about 1.5 fold higher in the presence of the R-isomers than in the presence of the S-isomers. For instance, at 2 mm DDT the reductase activities in the presence of 2.6 M R-and S-warfarin were about 15% of control. At 42mM DTT the activities were 90 and 65% of control, respectively. 5 In the in vitro experiments acenocoumarol appeared to be more potent than warfarin and phenprocoumon.6 The following mechanism is proposed: vitamin KO reductase becomes oxidized during substrate reduction. The oxidized (i.e. inactive) form binds equally to the R-and S-enantiomers of 4-hydroxycoumarins. The attached (covalently bound?) coumarin is released by the reactivation (i.e. reduction) of the enzyme. However, the rate of reactivation is strongly attenuated by the attached coumarin. This effect is more pronounced for the S-configuration of the 4-hydroxycoumarin anticoagulants.
The kinetics and dynamics of single doses (5 mg p.o.) of the optical isomers of acenocoumarol (R-AC and S-AC) were followed in healthy subjects and the effect on them of cimetidine 800 mg/day was also investigated. The AC enantiomers differed greatly in their pharmacokinetics. The mean residence time (MRT) of R-AC was about 10 times longer than that of S-AC, 15 h vs 1.2 h. There was no difference in the volume of distribution. Depression of blood clotting activity (Thrombotest) was observed only after administration of R-AC. The inactivity of S-AC as a vitamin K antagonist must be ascribed to its short MRT. Cimetidine did not affect the acute oral kinetics of R- and S-AC, nor did it affect the anticlotting activity of R-AC. The urinary excretion pattern of the 6- and 7-hydroxylated AC metabolites was not altered during cimetidine treatment. Although the present studies showed no effect of cimetidine on the pharmacokinetics and dynamics of acenocoumarol, the findings of Serlin et al. suggest that cimetidine should not be administered during acenocoumarol therapy.
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