Ammonia Toxicity

Ammonia Toxicity

• Ammonia is highly toxic. Even a marginal elevation in the blood ammonia concentration is harmful to the brain.
• Ammonia, when it accumulates in the body, results in slurring of speech and blurring of the vision and causes tremors.
• It may lead to coma and, finally, death, if not corrected.
• Normally blood ammonium concentration is < 50 µmol/L, and an increase to only 100 µmol /L can lead to disturbance of consciousness.
• A blood ammonium concentration of 200 µmol/L is associated with coma and convulsions.
• 200 µmol/L is far too low a concentration of ammonium to affect plasma pH or the normal transport of sodium and potassium ions across nerve cell membranes.

Hyperammonemia:

• Elevation in blood NH3 level may be genetic or acquired.
• Impairment in urea synthesis due to a defect in any one of the five enzymes is described in urea synthesis.
• All these disorders lead to hyperammonemia and cause hepatic comaand mental retardation.
• The acquired hyperammonemia may be due to hepatitis, alcoholism etc. where the urea synthesis becomes defective, hence NH₃ accumulates.

Mechanism of toxicity:

• The catabolic production of ammonia poses a serious biochemical problem because ammonia is very toxic.
• The brain is particularly sensitive; damage from ammonia toxicity causes cognitive impairment, ataxia, and epileptic seizures.
• In extreme cases, there is swelling of the brain leading to death.
• The molecular bases for this toxicity are gradually coming into focus.
• In the blood, about 98% of ammonia is in the protonated form (NH₄⁺), which does not cross the plasma membrane.
• The small amount of NH₃ present readily crosses all membranes, including the blood-brain barrier, allowing it to enter cells, where much of it becomes protonated and can accumulate inside cells as NH₄⁺.
• Ridding the cytosol of ammonia requires reductive amination of α– ketoglutarate to glutamate by glutamate dehydrogenase and conversion of glutamate to glutamine by glutamine synthetase.

• In the brain, only astrocytes—star-shaped cells of the nervous system that provide nutrients, support, and insulation for neurons—express glutamine synthetase.
• Accumulation of NH₃ shifts the equilibrium to the right with more glutamate formation,
  hence more utilization of α-ketoglutarate.
• α-Ketoglutarate is a key intermediate in TCA cycle and its depleted levels impair the TCA cycle.
• The net result is that the production of energy (ATP) by the brain is reduced.
• The toxic effects of NH3 on the brain are, therefore, due to impairment in ATP formation.
• Glutamate and its derivative γ-aminobutyrate are important neurotransmitters; some of the sensitivity of the brain to ammonia may reflect the depletion of glutamate in the glutamine synthetase reaction.
• However, glutamine synthetase activity is insufficient to deal with excess ammonia or to fully explain its toxicity.
• Increased [NH₄⁺] also alters the capacity of astrocytes to maintain potassium homeostasis across the membrane.
• NH₄⁺ competes with K⁺ for transport into the cell through the Na⁺K⁺ ATPase, resulting in elevated extracellular [K⁺].
• The excess extracellular K⁺ enters neurons through a symporter, Na⁺-K⁺-2Cl⁻ cotransporter 1 (NKCC1), bringing Na⁺ and 2Cl⁻ with it.
• Excess Cl⁻ in these neurons alters their response when the neurotransmitter GABA interacts with their GABA_A receptors, producing abnormal depolarization and increased neuronal activity that likely account for the neuromuscular incoordination and seizures that often result from ammonia poisoning.
• If extracellular [NH₄⁺] remains elevated, the perturbation of ion and aquaporin channels in astrocytes causes the cells to swell, resulting in fatal brain edema.

Medication (trapping and elimination of ammonia) :

• When the plasma level of ammonia is highly elevated, intravenous administration of sodium benzoate and phenyllactate is done.
• These compounds can respectively condense with glycine and glutamate to form water-soluble products that can be easily excreted.
• By this way, ammonia can be trapped and removed from the body.
• In some instances of toxic hyperammonemia, hemodialysis may become necessary.

References:

• Moran, L., Horton, R., Scrimgeour, G., Perry, M. and Rawn, D., 2013. Principles Of Biochemistry. Harlow: Pearson Education UK.
• Lehninger, A., Nelson, D. and Cox, M., 2013. Principles Of Biochemistry. 6th ed. New York: W.H. Freeman.
• Satyanarayana, U., 2014. Biochemistry. Elsevier Health Sciences APAC.
• Champe, P., Harvey, R. and Ferrier, D., 2008. Biochemistry. Philadelphia, Pa.: Wolters Kluwer / Lippincott Williams & Wilkins.
• Murray, R., Bender, D., Botham, K., Kennelly, P., Rodwell, V. and Weil, P., 2012. Harpers Illustrated Biochemistry. 29th ed. Blacklick: McGraw-Hill Publishing.
• Ucl.ac.uk. 2020. Untitled Document. [online] Available at: <https://www.ucl.ac.uk/~ucbcdab/urea/amtox.htm> [Accessed 25 May 2020].