ReviewCitrulline: From metabolism to therapeutic use
Introduction
Citrulline was first identified and isolated from the juice of the watermelon (Citrullus vulgaris) [1]. This amino acid initially attracted little interest because it is a non-protein amino acid that was considered solely an intermediate metabolite in ureagenesis [2], [3], but research into citrulline has surged over the past decade because of its very specific metabolism.
Because citrulline is synthesized almost exclusively by the intestine, plasma citrulline has been identified as a biomarker of the functional small bowel enterocyte mass (for recent reviews, see Crenn et al. [4] and Crenn and Cynober [5]). In addition, because the kidney is the main organ that metabolizes citrulline into arginine, renal failure is associated with impaired citrulline metabolism. An increase in plasma citrulline has been reported to be a potential marker of renal function [6]. These features highlight the major role of the intestine and kidneys in citrulline production and disposal, respectively.
Because it is a precursor of arginine, citrulline also is being investigated as a supplement from which arginine can be synthesized. Furthermore, in some cells, arginine can be recycled from citrulline, which is of major importance in the so-called nitric oxide (NO) cycle. Hence, citrulline can act as an arginine precursor for NO synthesis [7], and it plays an important role in NO metabolism and regulation [8]. Citrulline administration therefore may offer a therapeutic strategy for controlling NO metabolism disorders and improving cardiovascular function. Citrulline supplementation should be considered for use in all circumstances or disease states in which arginine has beneficial effects and/or where arginine supplementation may be considered harmful [9]. Furthermore, aging is associated with a high splanchnic sequestration of amino acids and sarcopenia [10], so citrulline, which escapes splanchnic extraction and can stimulate muscle protein synthesis [11], could be a valuable tool for delivering adequate amounts of nitrogen to peripheral tissues, including the muscle, in elderly subjects.
Citrulline administration thus has potential beneficial effects in various different situations. In this review article, we report experimental data from pharmacokinetic studies and clinical trials involving the oral administration of citrulline as an alternative to arginine. Because citrulline bioavailability is dependent on its intestinal absorption and because amino acid transport systems may regulate substrate availability for citrulline-requiring enzymes in the intestine, we start with a brief description of the citrulline amino acid transport systems.
Section snippets
Citrulline transport studies in intestinal models
In the rat intestine, citrulline absorption seems to be optimal between the median and lower ileum [12]. In addition, there is no evidence for an increased or decreased uptake of l-citrulline by enterocytes under low- or high-protein or l-citrulline intakes [8].
Citrulline transport is well characterized in several cell types (Table 1) [12], [13], [14], [15], [16], [17], but the mechanism of l-citrulline transport in the intestine remains poorly documented. There are only two relevant reports,
Pharmacokinetics of citrulline
Mandel et al. [1] studied the response of plasma citrulline and arginine to watermelon ingestion in healthy volunteers. After a one-time intake of watermelon, plasma concentrations of citrulline and arginine increased immediately after ingestion (Table 2) [31], [32], [33], [34], [35], [36], [37] but then decreased to baseline concentrations at 8 h after ingestion. This study is limited by an uncertainty as to the actual amount of citrulline ingested, but the mean citrulline intake was likely
Malnutrition associated to intestinal failure
Citrulline is lowered after a large intestinal resection, leading to intestinal failure [40], in villous atrophy [41], and in human immunodeficiency viral enteropathy [42]. Recent articles have discussed the value of the citrulline concentration as an indicator of acute intestinal failure in critically ill patients [43] or as a marker of bowel adaptation in children with short bowel syndrome [44]. Because citrulline and subsequently arginine concentrations are decreased in these situations,
Conclusion
The intestinal epithelium plays a central role in maintaining citrulline homeostasis by providing systemic citrulline. Citrulline is easily absorbed by the gut with a broad set of transporters as confirmed in pharmacokinetic studies. The major finding of these studies is that the oral administration of l-citrulline efficiently increases plasma l-arginine concentrations. Moreover, giving citrulline is more efficient at providing systemic arginine than giving arginine itself, likely because it
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