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MUCOSAL BIOLOGY

Manipulation of citrulline availability in humans

¹Unité mixte de recherche 1280, Physiologie des Adaptations Nutritionnelles, Institut National de la Recherche Agronomique and University of Nantes, Human Nutrition Research Center, Nantes; ²Néonatologie, Hôpital Mère-et-Enfant, Centre hospitalier universitaire (CHU) de Nantes; ³EA 3826, Thérapeutiques cliniques et expérimentales des maladies infectieuses, University of Nantes; ⁴Centre d'Investigation Clinique, Institut National de la Santé et de la Recherche Médicale and Centre hospitalier universitaire (CHU) de Nantes; and ⁵Biostatistiques, Pôle Information médicale, épidémiologie et santé publique, CHU de Nantes, Nantes, France

Submitted 25 June 2007 ; accepted in final form 20 September 2007

To determine whether circulating citrulline can be manipulated in vivo in humans, and, if so, whether citrulline availability affects the levels of related amino acids, nitric oxide, urinary citrulline, and urea nitrogen, 10 healthy volunteers were studied on 3 separate days: 1) under baseline conditions; 2) after a 24-h treatment with phenylbutyrate (0.36 g·kg^–1·day^–1), a glutamine "trapping" agent; and 3) during oral L-citrulline supplementation (0.18 g·kg^–1·day^–1), in randomized order. Plasma, erythrocyte (RBC), and urinary citrulline concentrations were determined by gas chromatography-mass spectrometry at 3-h intervals between 1100 and 2000 on each study day. Regardless of treatment, RBC citrulline was lower than plasma citrulline, with an RBC-to-plasma ratio of 0.60 ± 0.04, and urinary citrulline excretion accounted for <1% of the citrulline load filtered by kidney. Phenylbutyrate induced an 7% drop in plasma glutamine (P = 0.013), and 18 ± 14% (P < 0.0001) and 19 ± 17% (P < 0.01) declines in plasma and urine citrulline, respectively, with no alteration in RBC citrulline. Oral L-citrulline administration was associated with 1) a rise in plasma, urine, and RBC citrulline (39 ± 4 vs. 225 ± 44 µmol/l, 0.9 ± 0.3 vs. 6.2 ± 3.8 µmol/mmol creatinine, and 23 ± 1 vs. 52 ± 9 µmol/l, respectively); and 2) a doubling in plasma arginine level, without altering blood urea or urinary urea nitrogen excretion, and thus enhanced nitrogen balance. We conclude that 1) depletion of glutamine, the main precursor of citrulline, depletes plasma citrulline; 2) oral citrulline can be used to enhance systemic citrulline and arginine availability, because citrulline is bioavailable and very little citrulline is lost in urine; and 3) further studies are warranted to determine the mechanisms by which citrulline may enhance nitrogen balance in vivo in humans.

nutrition; gut; glutamine; protein metabolism