Hypoxanthine as an Indicator of Hypoxia: Its Role in Health and Disease through Free Radical Production

Hypoxia is a common insult during the perinatal and neonatal period.New and better ways to evaluate hypoxia are needed.In 1975 we demonstrated high concentrations of the purine metabolite hypoxanthine in umbilical cord plasma after intrauterine hypoxia and proposed that hypoxanthine could be used as an indicator of hypoxia (1).Since then a large number of studies have been published dealing with different aspects of hypoxanthine in hypoxia.However, investigators in this field have encountered several methodologic problems: 1) Hypoxanthine leaks rapidly from erythrocytes (2, 3); if plasma is not separated promptly from red cells, falsely elevated plasma hypoxanthine concentrations will be found.2) There are large variations in purine metabolism among species.3) No clear definition of clinical hypoxia is available.Many authors do not distinguish between the terms hypoxemia and hypoxia, which adds to the confusion.We define tissue hypoxia as: "oxygen deficiency resulting in altered or interrupted energy metabolism" (4).It is important to be aware that hypoxia has two stages.In the first stage it is compensated because the cells are able to meet energy demands through anaerobic metabolism and other mechanisms.(We are not dealing with physiologic adaptation to hypoxia.)In the second stage of hypoxia or uncompensated hypoxia, energy demands are not met and cell injury ensues.At present there are no techniques for distinguishing between these two stages in clinical medicine, and such a distinction would be useful.Theoretically hypoxanthine should only be elevated in uncompensated hypoxia, while pH and lactate changes occur in compensated hypoxia.It seems, however, that hypoxanthine is also elevated to some extent in uncompensated hypoxia.Renewed interest in hypoxanthine developed when it was realized that hypoxanthine is a potential free radical generator (5, 6).Hypoxanthine seems to play a role in posthypoxic reoxygenation cell injury through oxygen radical production (7) and is therefore involved in the pathogenesis of a number of diseases.Hypoxanthine also modulates a number of other processes because it reacts with benzodiazepine receptors (8) and inhibits phosphodiesterase in the brain (9).Hypoxanthine inhibits the effect of several cytotoxic drugs and may therefore influence treatment with such drugs (10).Herein we summarize the extensive literature on hypoxanthine published during the last decade and try to answer the question: How useful in clinical medicine are hypoxanthine measurements in plasma and other body fluids?Is hypoxanthine a better marker of hypoxia than lactate or pH?Further, we discuss the significance of hypoxanthine as a potential oxygen radical generator and put forward a hypothesis for the pathogenesis of an "oxygen radical disease in neonatology".