Ammonium ions toxicity

Martinelle K, Haggstrom L. 1993. Mechanisms of ammonia and ammonium ion toxicity in animal cells transport across cell membranes. J Biotechnol 30(3) 339-350. 

Amino groups released by deamination reactions form ammonium ion (NH " ), which must not escape into the peripheral blood. An elevated concentration of ammonium ion in the blood, hyperammonemia, has toxic effects in the brain (cerebral edema, convulsions, coma, and death). Most tissues add excess nitrogen to the blood as glutamine. Muscle sends nitrogen to the liver as alanine and smaller quantities of other amino acids, in addition to glutamine. Figure I-17-1 summarizes the flow of nitrogen from tissues to either the liver or kidney for excretion. The reactions catalyzed by four major enzymes or classes of enzymes involved in this process are summarized in Table T17-1. 

Ammonia (NH3) is a relatively strong base, and at physiological pH values it is mainly present in the form of the ammonium ion NH4 (see p. 30). NH3 and NH4 are toxic, and at higher concentrations cause brain damage in particular. Ammonia therefore has to be effectively inactivated and excreted. This can be carried out in various ways. Aquatic animals can excrete NH4 directly. For example, fish excrete NH4 via the gills (ammonotelic animals). Terrestrial vertebrates, including humans, hardly excrete any NH3, and instead, most ammonia is converted into urea before excretion ureotelic animals). Birds and reptiles, by contrast, form uric acid, which is mainly excreted as a solid in order to save water uricotelic animals). 

Using a macrocycle as a mobile phase additive is only practical for simple, inexpensive, relatively low-toxicity macrocycles such as 18-crown-6. A recent example of the benefits to be derived from addition of 18-crown-6 to an ion chromatographic eluent is found in work published by Lamb s group. [72] Specifically, in separating alkali, alkaline earth and amine cations by IC, it was found that addition of the macrocycle to the mobile phase could be used to adjust the retention time of ammonium cation so that ammonium ion could be determined under concentration ratios of 60,000 1 Na+ to NH4+ (see Figure 7). This method has specific application in the determination of ammonia produced by nitrogenase—analysis time and sample size are considerably reduced over traditional wet chemical methods. 

Recent observations have shown a direct relation between the pH of the blood and the depth of hepatic coma (VI). They are interpreted as evidence that the intracellular ammonia is increased in alkalosis because it is un-ionized ammonia and not ammonium ion which readily diffuses into cells. This finding may be a result of the central action of ammonium on the respiratory mechanism (F7), rather than the primary cause of the coma. In this sense it would seriously enhance the coma and set up a cycle which would be lethal. However this may be, there is no mechanism presented for the actual toxic effect of ammonia per se, and the data, except for the internal inconsistencies noted in a previous part of this discussion, would be compatible with the ketoglutarate depletion hypothesis. 

Ammonia (NH3) and the ammonium ion (NH4"1") are highly toxic to mammalian cells. In vivo, ammonium is secreted by the cells and transported to the mitochondria of hepatocytes, where it is converted into urea via the urea cycle. Urea production occurs almost exclusively in the liver and is the fate of most of the ammonium channeled there. The urea passes into the bloodstream and thus to the kidneys and is excreted into the urine. Mammalian cells in culture secrete ammonium into the culture medium, where its concentration increases gradually because there is no ammonium recycling pathway (Newland et al., 1990). 

Ammonia is toxic at high concentrations, even though ammonium ion, NH4+ is an intermediate in many reactions. For its utilization, ammonia must be incorporated into organic forms, transferred, and then incorporated into other compounds, for example, amino acids and nucleotides. The amino acids glutamine and glutamate and the compound carbamoyl phosphate are the key intermediates of nitrogen assimilation, leading to different classes of compounds. 

Pharmacokinetics Methenamine is orally administered. In addition to formaldehyde, ammonium ion is produced in the bladder. Because the liver rapidly metabolizes ammonia to form urea, methenamine is contraindicated in patients with hepatic insufficiency, in which elevated levels of circulating ammonium ions would be toxic to the CNS. Methenamine is distributed throughout the body fluids, but no decomposition of the drug occurs at pH 7.4 thus, systemic toxicity does not occur. The drug is eliminated in the urine. 

Equation 8.9 shows that when NH3 is introduced to an acid solution, it reacts directly with the acid and produces the ammonium ion (NH4) (see Chapter 12). Concurrent with Equation 8.9, NH3 may associate itself with several water molecules (NH3nH20) without coordinating another H+. This hydrated NH3 is commonly referred to as unionized ammonia and is toxic to aquatic life forms at low concentrations. Because NH3 is a volatile gas, some of it may be lost directly to the atmosphere (volatilization) without dissolving in solution. On the other hand, the ammonium ion may undergo various reactions in the soil water that may alter its availability to plants and/or other organisms. These reactions include formation of metal-ammine complexes, adsorption on to mineral surfaces, and chemical reactions with organic matter. 

McCarty and McKinney reported 18) that pH played a significant role in the toxicity of ammonium ion. They deduced that free ammonia... 

Ammonia and/or ammonium ion. This occurs to some extent in all organisms. However ammonia is quite toxic so it must be kept at low concentrations in the body. Thus ammonia is used as the major excretory product in organisms with an essentially unlimited amount of water available to dilute it plants, fish, many amphibians. 

Upon decomposition ammonium nitrate will release ammonium ions. Ammonia is a toxic hazard to fish and maybe harmful to animals on direct ingestion. Ammonium nitrate is nonpersistent and non-cumulative when applied using normal agriculture practices. It is not listed as a marine pollutant. 

This reaction is close to equilibrium in the liver, and the direction of the reaction is determined by the concentrations of reactants and products. Normally, the reaction is driven forward by the rapid removal of ammo-aium ion. Glutamate dehydrogenase is located in mitochondria, as are some of the other enzymes required for the production of urea. This compart-mentalization sequesters free ammonium ion, which is toxic. 

Oxidative deamination produces large amounts of ammonium ion. Because ammonium ions are extremely toxic, they must be removed from the body, regardless of the energy expenditure required. In humans, they are detoxified in the liver by converting the ammonium ions into urea. This pathway, called the urea cycle, is the method by which toxic ammonium ions are kept out of the blood. The excess ammonium ions incorporated in urea are excreted in the urine (Figure 22.12). 

The urea cycle converts ammonium ions into urea, which is less toxic. The sources of the atoms are shown in color and the intracellular locations of the reactions are indicated. Citrulline, formed in the reaction between ornithine and carbamoyl phosphate, is transported out of the mitochondrion and into the cytoplasm. Ornithine, a substrate for the formation of citrulline, is transported from the cytoplasm into the mitochondrion. 

In the urea cycle the toxic ammonium ions released by deamination of amino acids are incorporated in urea, which is excreted in the urine. 

---