Pegylated arginine deiminase depletes plasma arginine but maintains tissue arginine availability in young pigs

Authors: MOHAMMAD, MAHMOUD - Children'S Nutrition Research Center (CNRC); DIDELIJA, INKA - Children'S Nutrition Research Center (CNRC); STOLL, BARBARA - Children'S Nutrition Research Center (CNRC); NGUYEN, TRUNG - Baylor College Of Medicine; MARINI, JUAN - Children'S Nutrition Research Center (CNRC)

Submitted to: American Journal of Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/7/2021
Publication Date: 1/11/2021
Citation: Mohammad, M., Didelija, I., Stoll, B., Nguyen, T., Marini, J. 2021. Pegylated arginine deiminase depletes plasma arginine but maintains tissue arginine availability in young pigs. American Journal of Physiology. 320(3):E641-E652. https://doi.org/10.1152/ajpendo.00472.2020.
DOI: https://doi.org/10.1152/ajpendo.00472.2020

Interpretive Summary: In some disease processes (for example, during sepsis) or after trauma (including surgical trauma) the amino acid arginine is depleted in the circulation and tissues due to an increase in activity of the enzyme arginase. The administration of the compound ADI-PEG20 (Pegylated arginine deiminase) also results in the depletion of circulating arginine, which is converted to citrulline. This citrulline can be utilized by many tissues to produce intracellular arginine. Thus, the utilization of ADI-PEG20 preempts the action of arginase by removing arginine from the circulation. The citrulline produced from this reaction can be utilized by the citrulline directly by the tissues to produce local tissue arginine availability.

Technical Abstract: Pegylated arginine deiminase (ADI-PEG20) results in the depletion of arginine with the production of isomolar amounts of citrulline. This citrulline has the potential to be utilized by the citrulline recycling pathway regenerating arginine and sustaining tissue arginine availability. The goal of this research was to test the hypothesis that ADI-PEG20 depletes circulating arginine in pigs but maintains tissue arginine concentration and function, and to characterize the kinetics of citrulline and arginine. Two multitracer approaches (bolus dose and primed-continuous infusion) were used to investigate the metabolism of arginine and citrulline in Control (n = 7) and ADI-PEG20 treated (n = 8) pigs during the postprandial period. In addition, blood pressure was monitored by telemetry and multiple tissues collected to determine arginine concentration. Plasma arginine was depleted immediately after ADI-PEG20 administration, with an increase in plasma citrulline concentration (P < 0.01). The depletion of arginine did not affect (P > 0.10) blood pressure, whole body protein synthesis or urea production. Despite the lack of circulating arginine in ADI-PEG20 treated pigs, most tissues were able to maintain concentrations similar (P > 0.10) to those in Control animals. The kinetics of citrulline and arginine indicated the high citrulline turnover and regeneration of arginine through the citrulline recycling pathway. ADI-PEG20 administration resulted in an absolute and almost instantaneous depletion of circulating arginine thus reducing global availability without affecting cardio-vascular parameters and protein metabolism. The citrulline produced from the deimination of arginine was in turn utilized by the citrulline recycling pathway restoring local tissue arginine availability.