There is substantial clinical and experimental evidence that ammonia is a major factor in the pathogenesis of hepatic encephalopathy. In the article is demonstrated that in hepatocellular dysfunction, ammonia detoxification to glutamine (GLN) in skeletal muscle, brain, and likely the lungs, is activated. In addition to ammonia detoxification, enhanced GLN production may exert beneficial effects on the immune system and gut barrier function. However, enhanced GLN synthesis may exert adverse effects in the brain (swelling of astrocytes or altered neurotransmission) and stimulate catabolism of branched-chain amino acids (BCAA; valine, leucine, and isoleucine) in skeletal muscle. Furthermore, the majority of GLN produced is released to the blood and catabolized in enterocytes and the kidneys to ammonia, which due to liver injury escapes detoxification to urea and appears in peripheral blood. As only one molecule of ammonia is detoxified in GLN synthesis whereas two molecules may appear in GLN breakdown, these events can be seen as a vicious cycle in which enhanced ammonia concentration activates synthesis of GLN leading to its subsequent catabolism and increase in ammonia levels in the blood. These alterations may explain why therapies targeted to intestinal bacteria have only a limited effect on ammonia levels in patients with liver failure and indicate the needs of new therapeutic strategies focused on GLN metabolism. It is demonstrated that each of the various treatment options targeting only one the of the ammonia-lowering mechanisms that affect GLN metabolism, such as enhancing GLN synthesis (BCAA), suppressing ammonia production from GLN breakdown (glutaminase inhibitors and alpha-ketoglutarate), and promoting GLN elimination (phenylbutyrate) exerts substantial adverse effects that can be avoided if their combination is tailored to the specific needs of each patient.
- MeSH
- amoniak metabolismus MeSH
- enterocyty metabolismus MeSH
- fenylbutyráty škodlivé účinky farmakologie terapeutické užití MeSH
- glutamin metabolismus MeSH
- glutaminasa antagonisté a inhibitory MeSH
- hyperamonemie farmakoterapie etiologie metabolismus MeSH
- jaterní encefalopatie dietoterapie farmakoterapie metabolismus MeSH
- játra metabolismus MeSH
- kosterní svaly metabolismus MeSH
- kritický stav MeSH
- kyselina glutamová metabolismus farmakologie terapeutické užití MeSH
- kyseliny ketoglutarové škodlivé účinky farmakologie terapeutické užití MeSH
- ledviny metabolismus MeSH
- lékové interakce MeSH
- lidé MeSH
- mikrobiota MeSH
- mozek metabolismus MeSH
- orgánová specificita MeSH
- střeva mikrobiologie MeSH
- větvené aminokyseliny metabolismus terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Oxidative stress may cause free radical reactions to produce deleterious modifications in membranes, proteins, enzymes and DNA. Valproic acid is a major anti-epileptic drug with a broad spectrum of antiepileptic activity. Chronic treatment with valproic acid can lead to elevated serum ammonia levels and specific oxidative metabolites of valproic acid have been associated with the drug's toxicity. The influence of sodium valproate treatment on lipid peroxidation and lipid profiles and the detoxifying effects of ?-ketoglutarate on sodium valproate induced toxicity were studied in rats. The levels of thiobarbituric acid reactive substances, hydroperoxides and lipid profile variables (cholesterol, phospholipids, triglycerides and free fatty acids) were significantly increased in sodium valproate treated rats. Further, non-enzymic antioxidants (reduced glutathione) and the activities of the enzymic (superoxide dismutase, catalase, glutathione peroxidase) antioxidants were significantly decreased in sodium valproate treated rats. The levels were observed to be normal in ?-KG + sodium valproate treated rats. These biochemical alterations during ?-KG treatment could be due to (i) its ubiquitous collection of amino groups in body tissues, (ii) the participation of ?-KG in non-enzymatic oxidative decarboxylation of the hydrogen peroxide decomposition process and (iii) its role in the metabolism of fats which could suppress oxygen radical generation and thus prevent lipid peroxidative damage.
- MeSH
- antioxidancia metabolismus MeSH
- experimenty na zvířatech MeSH
- interpretace statistických dat MeSH
- krysa rodu rattus metabolismus MeSH
- kyselina valproová analogy a deriváty aplikace a dávkování terapeutické užití MeSH
- kyseliny ketoglutarové aplikace a dávkování terapeutické užití MeSH
- oxidační stres účinky záření MeSH
- peroxidace lipidů účinky záření MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus metabolismus MeSH
- zvířata MeSH
