Ornithine is the non-essential amino acid that is one of the most important carriers of the nitrogen in the urea cycle — it is the central intermediate in the urea cycle, where it accepts the ammonia from the aspartate and from the glutamine and delivers it to the carbamoyl phosphate for the conversion to the citrulline and then to the arginine and back to the ornithine. The ornithine is unique among the amino acids because it is not incorporated into the proteins — it is a free amino acid that is involved exclusively in the urea cycle and in the polyamine synthesis. The ornithine is produced in the urea cycle from the arginine (through the arginase reaction, which cleaves the arginine to produce the ornithine and the urea), and it is converted back to the arginine (through the ornithine transcarbamylase reaction, which combines the ornithine with the carbamoyl phosphate to form the citrulline). Without adequate ornithine and urea cycle function, the ammonia accumulates in the blood, the hepatic encephalopathy develops, and the sleep is disturbed — the hallmark of the ornithine deficiency and of the impaired urea cycle function. The typical dietary ornithine intake from the protein-rich foods (meat, fish, poultry, eggs, dairy) is 0.5-2g daily, and the body can synthesise sufficient ornithine from the arginine to meet the needs of most people — making it a non-essential amino acid, but one that may become conditionally essential during the periods of the high protein catabolism, the liver disease, or the urea cycle disorders.
Ornithine and the Ammonia Detoxification
Ornithine supports the ammonia detoxification primarily through its role in the urea cycle — the urea cycle is the primary mechanism by which the ammonia (which is a toxic byproduct of the amino acid metabolism) is converted to the urea and excreted in the urine. The ornithine is the carrier of the nitrogen in the urea cycle — it accepts the ammonia from the aspartate (through the argininosuccinate synthetase reaction) and from the glutamine (through the carbamoyl phosphate synthetase I reaction), and it delivers this nitrogen to the carbamoyl phosphate to form the citrulline. The ornithine therefore sits at the centre of the urea cycle, and it is the rate-limiting factor for the urea synthesis when the ammonia levels are high. The ornithine supplementation has been shown in multiple studies to reduce the blood ammonia levels and to improve the symptoms of the hepatic encephalopathy in people with the liver cirrhosis and with the urea cycle disorders — making it one of the most important interventions for the hyperammonemia and for the protection of the CNS from the ammonia toxicity.
The clinical importance of the ornithine for the ammonia metabolism is underscored by the observation that the ornithine supplementation reduces the blood ammonia and improves the cognitive function in people with the liver cirrhosis and with the hyperammonemia. A study in 20 patients with the liver cirrhosis found that the ornithine supplementation at 3g daily for 4 weeks significantly reduced the fasting blood ammonia (by 25-30%), improved the cognitive function (by 15-20%, as measured by the trail-making test and the digit symbol substitution test), and improved the sleep quality (by 15-20%) — demonstrating the potent ammonia-lowering and neuroprotective effect of the ornithine in patients with the impaired liver function.
Practical Application
For general ornithine supplementation for the ammonia metabolism and for the liver support, the evidence-based approach is to supplement with 1-3g of L-ornithine daily (as the L-ornithine HCl or the L-ornithine-L-aspartate, which are the most common forms of the ornithine supplement). The ornithine should be taken on the empty stomach (30-60 minutes before the meals or 2 hours after the meals) for the optimal absorption, and it should be taken with the arginine and the citrulline (which are the other key intermediates in the urea cycle and which work synergistically with the ornithine for the ammonia disposal). The ornithine is generally well-tolerated with no significant adverse effects at doses up to 6000mg daily, though it may cause the gastrointestinal symptoms (nausea, diarrhoea) at the high doses. For comprehensive ammonia metabolism and liver support, ornithine pairs well with the arginine (which is the precursor of the ornithine in the urea cycle and which is a vasodilator that supports the liver blood flow), with the aspartic acid (which is the source of the nitrogen that is carried by the ornithine in the urea cycle), with the alpha-ketoglutarate (which is a cofactor for the glutamate dehydrogenase reaction and which helps to dispose of the ammonia through the conversion to the glutamate), and with the zinc (which is a cofactor for the ornithine transcarbamylase and for the other enzymes of the urea cycle).
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