Resultados generales sobre los Recursos Hídricos

The central role of the small intestine in the metabolism of glutamine was firmly established by the studies of Windmueller and Spaeth (1974) using isolated perfused small intestinal preparations. Their work revealed that citrulline was one of the many compounds generated by the metabolism of the gut. Since then, glutamine has been considered the main precursor for citrulline synthesis (Fujita and Yanaga, 2007; Deutz, 2008) and tracer studies utilizing 2-15_{N (amino) glutamine seem} to indicate that 60-80% of citrulline originates from glutamine (Boelens et al., 2005; Boelens et al., 2006; Ligthart-Melis et al., 2007; Ligthart-Melis et al., 2008).

The labeling of glutamine with 15_{N, however, does not follow the carbon skeleton of glutamine and} thus no precursor-product relationship can be established using this tracer (Marini et al., 2010b).

Likewise, the incorporation of 14_{C from glutamine into citrulline (Windmueller and Spaeth, 1974) is} not proof that the carbon skeleton of glutamine is used to synthesize citrulline, since CO₂ generated from the oxidation of glutamine, can be incorporated into the ureido group. In fact, it has been shown that U-14_{C glutamate is incorporated into arginine in neonatal piglets (Murphy et al., 1996),} but [3,4] 3_{H glutamate is not (Wilkinson et al., 2004). It is worthwhile to mention that Windmueller} and Spaeth (1974, 1981) explicitly pointed out that citrulline was an end product of glutamine nitrogen metabolism.

Proline seems to be utilized for the synthesis of citrulline and arginine because proline ameliorates arginine deficiency in neonatal piglets (Brunton et al., 1999). The first pass enteral utilization of proline has been shown to be more efficient, since intragastric tracers result in a higher enrichment of arginine than femoral (Murphy et al., 1996) or portal infused tracers (Bertolo et al., 2003). Furthermore, the gut atrophy that results from parenteral nutrition, in combination with the reduced uptake of plasma proline, could explain the low rate of plasma proline utilization for the synthesis of arginine in piglets (Urschel et al., 2007a).

The production of ornithine from arginine is thought not to occur during the neonatal period due to the reported lack of arginase activity in enterocytes (Wu, 1995). This has been confirmed in neonatal piglets because, despite an extensive first pass enteral utilization of arginine (~40%), no labelled urea was generated when an arginine tracer was infused intragastrically (Bertolo et al., 2003). In the adult, however, a similar enteral utilization of arginine is accompanied by the release of urea and ornithine, and the use of arginine for the synthesis of citrulline (Windmueller and Spaeth, 1976). In both adults and neonates, arginine can generate ornithine in other tissues besides the gut and then serve as precursor for citrulline (and arginine) synthesis. In fact this arginine-arginine cycle has been reported in neonatal piglets (Urschel et al., 2005), humans (Beaumier et al., 1995) and mice (Marini, 2010b,c) and accounts for up to 35% of the arginine flux when arginine is deficient in the diet (Urschel et al., 2005). The utilization of plasma ornithine for citrulline synthesis accounts for 15-30% of the citrulline flux in adult humans (Castillo et al., 1994; Beaumier et al., 1995) and mice (Marini et al., 2010a,c). Likewise, neonatal piglets have shown substantial utilization of plasma ornithine for citrulline and arginine synthesis, as well as intragastrically infused ornithine (Bertolo

et al., 2003; Urschel et al., 2007c). In fact, it has been shown that ornithine tracers are more readily

used for citrulline synthesis than proline tracers (Urschel et al., 2007b). Therefore, it seems that there is a preferential utilization of ‘preformed’ rather than ‘de novo’ ornithine for citrulline synthesis. The utilization of arginine for the synthesis of the ornithine used in citrulline synthesis seems to be a futile cycle and it has no apparent purpose. It has been shown that citrulline synthesis can be maintained exclusively utilizing endogenous precursors, since a 4 week deprivation of proline, glutamine/glutamate and arginine did not reduce the rate of citrulline synthesis nor increased amino acid oxidation (Tharakan et al., 2008). Which endogenous precursors for citrulline synthesis are used in these conditions remains to be answered.

Since the discovery of citrulline and its functions as intermediate in the urea cycle and as precursor for arginine synthesis, much knowledge has been accumulated on the different aspects of citrulline metabolism. However, the integration of the processes involved at the whole animal and human level has lagged behind. The absence of the intestinal-renal axis for arginine synthesis in neonates, for instance, is based on the presence of the cytosolic enzymes of the urea cycle in the enterocyte. That the kidney presents the same enzymes, albeit at a reduced activity than in adulthood, and that circulating citrulline concentrations are not different than later in life has been ignored. Also, there is no consensus in the literature regarding the precursors for citrulline synthesis. Part of the apparent conflict resides in the fact that the in vitro data cannot be directly extrapolated to the whole organism. Moreover, in vivo determinations should be considered carefully, since some tracer studies do not take into account the incorporation of the label after tracer oxidation and thus no precursor-product

can be established. More research is needed in order to integrate enzymatic expression and activity of different tissues with the interorgan trafficking of precursor and urea cycle intermediates. Urea cycle disorder patients and mouse transgenic models offer the possibility to study the impact of specific enzyme deletions on the metabolism of citrulline in vivo. Furthermore, the advent of tissue specific knockout mouse models further expands our ability to probe the role and contribution of different tissues and cell types in the economy of citrulline and arginine.

Acknowledgments

This work was supported by USDA 2533771314 and NIH KO1 RR24173.

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