Detoxification ammonia

Both compounds inhibit glutamine synthetase, which is necessary for the production of glutamine and for ammonia detoxification. Plants that are exposed to glufosinate have reduced glutamine and increased ammonia levels in their tissues, which stops photosynthesis and results in death within a few days. Other natural products (e.g. tabtoxine- -lactam, oxetin, and methionine sufoximine) are known to have this mode of action, but they have not been developed as commercial products. 

Urea Formation Is a Complex and Costly Mode of Ammonia Detoxification... 

Classic citrullinaemia Argininosuccinate synthetase Episodic hyperammonaemia, vomiting, lethargy, ataxia, seizures, eventual coma. Treatment is with arginine administration to enhance citrulline excretion, also with sodium benzoate for ammonia detoxification. 

Fig. 3.12 Diagram showing the ammonia detoxification process in the urea cycle (= ornithine cycle) (H.A. Krebs, K. Henseleit, 1932) (A.L. Lehnesigee, 1979)...

The urea cycle, also called ornithine cycle, was first described by H.A. Krebs and K. Henseleit in 1932. (quot. 51) The principle of ammonia detoxification in the urea cycle is based on the conversion of ammonium and bicarbonate in the mitochondria under ATP consumption into carbamoyl phosphate (by means of carbamoyl phosphate synthetase). It enters the urea cycle, which is localized mainly - yet with a low affinity for ammonium - in the periportal zone of the liver lobule. In the urea cycle alone, about two thirds of the amino nitrogen of ammonia are irretrievably lost to the organism (= definitive ammonia detoxification), (s. fig. 3.12)... 

The remaining third of the ammonia is trapped by the peripheral hepatocytes (= scavenger cells) due to their high affinity. By means of glutamine synthetase, glutamine is formed as a nontoxic transport form of ammonia. At the same time, it also serves to activate the urea cycle (= temporary ammonia detoxification), (s. fig. 3.13)... 

As a rule, 2 mol bicarbonate are required for the synthesis of 1 mol urea. The amount of urea eliminated in the urine is approximately 500 mmol/day (ca. 30 g). Normally, only about 25% of the capacity of the urea cycle are used. It is therefore virtually impossible for hyperammonaemia to be a sequela to isolated NH4+ hyperproduction alone. In patients with liver cirrhosis, the capacity for urea synthesis is reduced by approximately 80%, i. e. there is a considerable decrease in ammonia detoxification in the periportal field, predominantly due to a function loss on the part of the perivenous scavenger cells. 

Of particular significance is the serious impairment of essential tasks performed by the liver such as the detoxification function (ammonia detoxification, biotransformation, radical scavenger function, clearance abilities of the RES, etc.), the synthesis of vital proteins and the regulation of biochemical systems and substances — these are considered to be precursors of complicative developments. Any insufficiency of bilirubin metabolism is reflected in increasing jaundice, likewise deemed to be an unfavourable sign with respect to prognosis. 

Primary pulmonary diseases (e.g. primary pulmonary hypertension, pulmonary fibrosis, chronic obstructive respiratory diseases) cause chronic hepatic congestion due to chronic pulmonary heart disease, possibly leading to insufficiency. Hypoxaemia as a result of acute or chronic respiratory insufficiency can impair metabolic liver functions considerably. In 40—70% of patients with cirrhosis, hypoxaemia can be found in about 50% of cases with advanced cirrhosis, a reduced diffusion capacity for CO is detectable. Furthermore, pulmonary tissue contains a high level of glutamine synthetase, so that ammonia detoxification is possible (ultimately by perivenous hepatocytes) before the blood reaches the systemic circulation. In existing pulmonary diseases, localized ammonia detoxification is impaired. 

The indication for administering BCAA in patients with hepatic encephalopathy to compensate amino-acid imbalance was proposed by J.E. Fischer et al. in 1974, and implemented parenterally. However, oral application of BCAA for an adequate treatment period also has beneficial effects on cirrhosis and HE (7.) improvement in protein tolerance and the nutritional condition, (2.) improvement in cerebral functions (II8, 122), probably due to an amelioration of liver function, (2.) stimulation of ammonia detoxification with a positive nitrogen balance (118), (4.) reduction in or normalization of AAA levels, and (5.) promotion of glutamine synthesis with a favourable effect on the cells of the immune system and on renal function. By means of BCAA, it was possible to prolong the survival time and delay the occurrence of liver failure in rats with CC -induced cirrhosis. (123, 126) However, there are diverging results, which need further clarification. In principle, the use of BCAA is considered to be a necessary form of supplementary treatment for catabolic metabolism in cirrhosis (124,125, 127, 128, 130-132), in (also latent) HE and after curative resection of hepatocellular carcinoma. (I2l) (s. p. 280)... 

The biomolecular modes of action of ornithine have been the subject of several experimental investigations. Ornithine activates the enzymes carbamylphosphate synthetase and ornithine carbamyl transferase, which are necessary for the liver-specific process of urea synthesis (133,139) this occurs mainly in the periportal hepa-tocytes (= definitive ammonia detoxification). Glutamine synthesis (binding of ammonia to glutamate) takes place predominantly in the perivenous hepatocytes (= transitory ammonia detoxification). Large amounts of glutamate are necessary for this. Aspartate, ornithine... 

Centrilobular zone/Zone 3 Glucose uptake Ammonia detoxification Biotransformation reactions... 

Unlike the liver, skeletal muscle and brain are devoid of an effective urea cycle and consequently must rely on glutamine synthesis for ammonia removal. In Uver failure, muscle becomes the major route for ammonia detoxification. Evidence consistent with this notion includes reports of increased glutamine production by skeletal muscle in chronic liver insufficiency (Ganda and Ruderman, 1976). More recently it has been shown that chronic hyperammonemia resulting from portacaval... 

Fig. 9.3 Effect of liver failure on inter-organ trafficking of ammonia. Under normal physiological conditions, ammonia produced by the gut is removed by the liver as urea (periportal hepatocytes) or glutamine (perivenous hepatocytes). Increased ammonia synthesis by the kidney is offset by increased urinary ammonia excretion. In liver failure, skeletal muscle becomes the major route for ammonia detoxification as a result of a post-translational increase of glutamine synthetase. Unlike muscle, the brain does not adapt to liver failure by induction or glutamine synthetase...

Occurrence NH3 is the end product of the degradation of nitrogen-containing organic matter. It therefore occurs as ammonium salts in the soil. In animals NH3 is eliminated by detoxification reactions (see Ammonia detoxification), while in plants and bacteria it is assimilated for the synthesis of nitrogenous compounds. The concentration of ammonium ions in body fluids and all living cells is therefore relatively low. 

Table 1. Forms of ammonia detoxification and nitrogen excretion...

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