Ornithine by Ray Sahelian, M.D.
Ornithine or L ornithine is an amino Acid used by the body to make arginine, proline, and polyamines. Ornithine is not an amino acid coded for by DNA, and is not involved in protein synthesis. Ornithine, therefore, is not found in protein.
Ornithine can be made as a byproduct when the enzyme arginase metabolizes arginine to urea. Hence, ornithine is a prominent part of the urea cycle, which allows for the disposal of excess nitrogen. Most commonly, nitrogen is ingested through foods that contain protein.
The Urea Cycle
The main use of the urea cycle is to make arginine, so as an intermediate in metabolic processes, ornithine is quite
important. Ornithine, via the action of ornithine decarboxylase, is the starting
point for the synthesis of polyamines such as putrescine.
Ornithine decarboxylase (ODC) is a key enzyme in polyamine biosynthesis. Increased polyamine levels are required for growth, differentiation, and transformation of cells.
Arginine Versus Ornithine
Ornithine supplementation may be helpful in cases of burn injury and
wound healing. At present, I don't have enough of an understanding of ornithine
to know under which circumstances it would be appropriate to supplement with it.
Since ornithine can be made from arginine, supplementation with
arginine may be
sufficient or a good replacement. You may also consider ornithine alpha
ketoglutarate supplements.
Ornithine alpha-ketoglutarate (OKG) information
Ornithine alpha-ketoglutarate is a salt formed of
2 molecules of ornithine and 1 alpha-ketoglutarate. Its administration improves
nutritional status in chronically malnourished (e.g., elderly) and acutely
malnourished patients (especially burn and trauma patients). There is evidence
that OKG activity is not the simple addition of the effects of ornithine
and alpha-ketoglutarate (alphaKG), because the presence of both moieties is
required to induce the generation of key metabolites such as glutamine, proline,
and arginine, whereas this does not occur when one or the other is given
separately. For years, ornithine alpha-ketoglutarate activity
has been associated with its ability to induce the secretion of anabolic
hormones, such as insulin and growth hormone, and to increase glutamine and
polyamine synthesis. Recent studies using chemical inhibitors of nitric oxide synthase (NOS) suggest that nitric oxide derived from
arginine could be partly
involved in OKG activity.
Theoretically, alpha-ketoglutarate is a precursor of glutamine, a fact that may be of importance given the key regulatory properties of this amino acid. Although the literature suggests that glutamine synthesis accounts only for a marginal part of the disposal of exogenously supplied alpha-ketoglutarate, administered alpha-ketoglutarate has a potent 'sparing' effect on endogenous glutamine pools. When alpha-ketoglutarate is supplied as an ornithine salt, a synergistic effect of the two parts of the molecule increases the synthesis of glutamine or the 'sparing' of endogenous glutamine pools. In addition, alpha-ketoglutarate in combination with ornithine dramatically increases the synthesis of arginine, proline and polyamines, which also play key roles in metabolic adaptation to trauma. The administration of alpha-ketoglutarate in combination with ornithine improves gut morphology and functions, counteracts trauma-induced dysimmunity and exerts anabolic/anticatabolic actions on protein metabolism.
Coadministration of Ornithine and alpha-Ketoglutarate Is No More Effective Than
Ornithine Alone As an Arginine Precursor in Piglets Enterally Fed an Arginine-Deficient
Diet.
J Nutr. 2007 Jan;137(1):55-62. Urschel KL, et al. Department of
Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB,
Canada T6G 2P5; 3The Research Institute, The Hospital for Sick Children,
Toronto, ON, Canada M5G 1X8 the Departments of 4Paediatrics and 5Nutritional
Science, University of Toronto, Toronto, ON, Canada M5G 1X8.
Simultaneous administration of alpha-ketoglutarate and ornithine, in a 1:2 molar
ratio, may improve the effectiveness of ornithine as an arginine precursor in
neonatal piglets by shifting ornithine metabolism away from oxidation and toward
the synthesis of arginine and other metabolically important compounds. To study
this proposed mechanism, enterally fed piglets were allocated to receive 1 of 4
diets for 5 d: an arginine -deficient diet (basal), or the basal diet
supplemented with either alpha-ketoglutarate, ornithine, or both ornithine and
alpha-ketoglutarate. The diets did not affect plasma arginine or ammonia
concentrations, arginine flux, or arginine synthesis from ornithine. Therefore,
arginine synthesis was not increased by the simultaneous infusion of ornithine
and alpha-ketoglutarate. Piglets that received dietary ornithine had a 2-fold
greater rate of proline synthesis from ornithine and oxidized a greater portion
of the infused ornithine than piglets in the basal and +alpha-KG groups.
Overall, ornithine addition to an arginine deficient diet had a greater effect
on ornithine and arginine metabolism than the addition of alpha-ketoglutarate.
First-pass intestinal metabolism was critical for ornithine synthesis and
conversion to other metabolites but not for ornithine oxidation.
Ornithine, Arginine, and Human Growth Hormone release
Certain amino acids, such as arginine and ornithine, can stimulate
the release of growth hormone when infused intravenously or administered orally.
Some individuals ingest amino acids before strength training workouts,
thinking that this enhances exercise-induced growth hormone release, thereby
promoting greater gains in muscle mass and strength. There is a wide range of
response of growth hormone release to amino acid administration between
different people. A number of factors are involved including training status, sex, age,
medications, other supplements, and diet. Although IV
administration consistently leads to increased circulating growth hormone concentration,
oral doses that are great enough to induce significant growth hormone release are likely to
cause stomach discomfort and diarrhea. Ornithine may have to be ingested in
massive amounts, such as 30 grams orally, to have any effect on growth hormone
release, and even then, the release may be temporary.
During exercise, intensity is a major
determinant of growth hormone release. Up to now, studies have not consistently
found that pre-exercise oral amino acid supplementation enhances growth hormone release.
In addition,, no major studies have found that oral supplementation with arginine or ornithine before strength training increases
muscle mass and strength to a greater extent than strength training alone. The
use of specific amino acids to stimulate growth hormone release by athletes is
probably not worthwhile.
Ornithine transcarbamylase deficiency
Let's discuss the symptoms and signs of ornithine transcarbamylase deficiency. When the condition occurs among males in the neonatal period it is likely to be lethal. When hyperammonaemia is found, enzyme assay on a liver biopsy should be considered. A useful clue in an asymptomatic patient is a voluntary adoption of a vegetarian diet. The prognosis of ornithine transcarbamylase deficiency is better for those with an onset after infancy. The syndrome results from a deficiency of the mitochondrial enzyme ornithine transcarbamylase which catalyses the conversion of ornithine and carbamoyl phosphate to citrulline. There can be a variety of precipitating causes, for example sodium valproate. Treatment can be given with a low protein diet, and with alternate pathway drugs such as sodium benzoate and phenylbutyrate. Liver transplant can be considered when symptoms are life-threatening, although there may be severe complications.
L Ornithine Research Update
Clinical efficacy of L-ornithine-L-aspartate in the
management of hepatic encephalopathy.
Metab Brain Dis. 2002 Dec;17(4):453-62.
The clinical efficacy of both oral and parenteral L-ornithine-L-aspartate (OA)
was confirmed by randomized, placebo-controlled, double-blind studies in
patients with manifest hepatic encephalopathy and hyperammonemia. The drug was
able to reduce high blood ammonia levels induced either by ammonium chloride or
protein ingestion or existing as a clinical complication of cirrhosis per se.
Furthermore, OA improved performance in Number Connection Test-A as well as
mental state gradation. In contrast to the positive effects observed in patients
with more advanced hepatic encephalopathy, oral OA does not seem to affect
minimal hepatic encephalopathy. In a recent trial, OA decreased protein
breakdown and stimulated protein synthesis in muscle. The therapy had little
side effects, increasing with higher intravenously administered dosages, and was
well tolerated after oral and parenteral administration.
Cancer therapy and prevention by green tea: role of
ornithine decarboxylase.
Amino Acids. 2002;22(1):1-13.
Epidemiological studies revealed that the incidences of
stomach and prostate cancers are the lowest in the world among a population that
consumes green tea on a regular basis. It has also been reported that the
quantity of green tea consumed, plays an important role in reducing cancer risk
and in delaying cancer outbreak and recurrence. Various systems were used to
confirm anti-cancer activities of green tea and/or EGCG. These included
experimental animals in which cancer was induced chemically. Cultured cells
transformed chemically or by oncogenes were also used. These studies clearly
demonstrated that green tea or EGCG have anticancer and cancer preventive
properties. The mechanisms of these activities have also been studied in
details. It has been shown that green tea and its active components interfere
with signal transduction pathways. Thus the activities of various protein
kinases are inhibited, the expression of nuclear proto-oncogenes declines and
the activity of ornithine decarboxylase (ODC) is reduced. ODC, which catalyzes
the rate-limiting step in the biosynthesis of polyamines is closely linked with
cellular proliferation and carcinogenesis. Inhibitors of ODC, like alpha-difluoromethylornithine
(DFMO) have long been used for cancer prevention and therapy. It has been
suggested that polyamine depletion by green tea could offer one explanation for
its anti-cancer activities.
Macrophage arginine metabolism to ornithine/urea or
nitric oxide/citrulline: a life or death issue.
Crit Rev Immunol. 2001;21(5):399-425. Mills CD.
Department of Surgery and Diabetes Institute for Immunology and Transplantation,
University of Minnesota Hospitals and Clinics, Minneapolis
Macrophages can metabolize arginine to nitric oxide in quantities that inhibit
pathogens or nearby host cells. They can instead metabolize arginine to
ornithine (a precursor of polyamines and collagen) in quantities that stimulate
pathogens or nearby host cells. Macrophages are essentially the only circulating
cells that can make these life or death decisions with arginine. Macrophages
expressing these destructive or constructive phenotypes have been termed M-1 or
M-2 because they also stimulate TH1 or TH2 responses, respectively. Factors that
influence whether a macrophage expresses the M-1 or M-2 phenotype and the real
or potential impact on immune responses and other host processes are discussed.
Can arginine and ornithine support gut functions?
Gut. 1994 Jan;35(1 Suppl):S42-5.
Arginine and ornithine are precursors of nitric oxide and polyamines,
respectively. These metabolites intimately participate in permeability and
adaptive responses of the gut. The liver possesses high arginase activity as an
intrinsic part of urea synthesis and would consume most of the portal supply of
dietary arginine. The gut reduces this possibility by converting dietary
arginine to citrulline, which effectively bypass the liver and is resynthesized
to arginine in the kidney. Dietary ornithine supplementation, in the form of
ornithine alpha-ketoglutarate (OKG) can be considered as an arginine precursor.
Several supplement studies have shown both amino acids to promote growth hormone
and insulin secretion with anabolic effects in postoperative patients. Their
intermediary metabolites (for example, glutamine, proline) may also be of
benefit in trauma metabolism. Specific effects of either amino acid on the gut
are poorly reported. One recent animal study showed improved morphology after
OKG administration, perhaps through increased polyamine secretion. Generation of
nitric oxide from arginine has two facets. Excess production from high dose
arginine potentiated the effects of experimentally induced sepsis, whereas low
doses improved survival. These considerations suggest that the role of enteral
diet supplementation with arginine or OKG should be urgently examined for any
benefits it may have on mucosal barrier function.