Citrulline is an intermediate, nonprotein-forming amino acid in the urea cycle serving as a precursor to arginine. It derives its name from the watermelon (Citrullus vulgaris), where it was first isolated and identified. It is easily absorbed by the gut and bypasses the liver, making it an effective method for repleting arginine.
Other food sources of citrulline include muskmelons, bitter melons, squashes, gourds, cucumbers and pumpkins. Citrulline can also be synthesized from arginine and glutamine in enterocytes, which can then be metabolized by the kidneys back into arginine. Because citrulline is produced in enterocytes, it has been proposed as a marker of enterocyte mass in conditions of villous atrophy.
Given the importance of arginine in nitric oxide production for vasodilation and muscle protein synthesis, citrulline is sometimes administered therapeutically to deliver arginine to endothelial and immune cells. It is also supplemented in sarcopenia to stimulate protein synthesis in skeletal muscle through the rapamycin (mTOR) pathway. Citrulline supplementation has been studied in conditions like erectile dysfunction, sickle cell anemia, short bowel syndrome, hyperlipidemia, cancer chemotherapy, urea cycle disorders, Alzheimer’s disease, multi-infarct dementia, and as an immunomodulator.
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- Allerton TD, Proctor DN, Stephens JM, Dugas TR, Spielmann G, Irving BA. l-Citrulline Supplementation: Impact on Cardiometabolic Health. Nutrients. 2018;10(7).
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- Crenn P, Vahedi K, Lavergne-Slove A, Cynober L, Matuchansky C, Messing B. Plasma citrulline: A marker of enterocyte mass in villous atrophy-associated small bowel disease. Gastroenterology. 2003;124(5):1210-1219.
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Low citrulline may be secondary to a relatively low protein diet and/or intestinal malabsorption. Because citrulline can be formed from glutamine, glutamine depletion has been associated with low citrulline levels in plasma.
Elevated citrulline can occur with urea cycle defects. Lack of nutrient cofactors or enzymatic SNPs within the urea cycle can contribute to elevated citrulline levels. Citrullinemia is an inherited autosomal recessive disease that affects the enzyme arginosuccinate synthase and is diagnosed in infancy. In most cases, a serious problem related to citrulline is unlikely and may be a limitation in the cofactors associated with citrulline metabolism: aspartic acid and magnesium.
Elevated plasma levels may result from citrulline supplementation. Orally administered citrulline is highly bioavailable since plasma levels rise dramatically, whereas urinary citrulline loss is minimal. Elevated citrulline in urine can be a consequence of a urinary tract infection where bacterial action reduces arginine and produces citrulline. Administration of thiamine (vitamin B1) has been found to lower elevated citrulline, as well as other amino acids, in thiamine deficiency.
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