Ammonia

Ammonia (NH3) is a compound composed of nitrogen and hydrogen. It is found in trace amounts in the atmosphere and is a major component of the nitrogen cycle. It is also produced naturally by living organisms as a by-product of metabolism. To the human body, ammonia is toxic and corrosive {ref}.

How ammonia promotes cell proliferation and angiogenesis, and alters metabolic pathways, contributing to cancer growth.

The involvement of ammonia in the growth and spread of cancer is intricate and not fully understood. Ammonia can act as a signal for cell proliferation due to its ability to activate certain pathways in the cell, such as the mitogen-activated protein kinase or MAPK pathway. This pathway is involved in the regulation of cell growth, proliferation, differentiation and apoptosis. In addition, ammonia can activate the PI3K/Akt pathway, which is involved in cell survival and growth.

Ammonia can also promote angiogenesis {ref}, which is the formation of new blood vessels. This is due to its ability to activate certain pathways, such as the previously mentioned PI3K/Akt pathway. This pathway can increase the expression of certain angiogenic factors, such as VEGF. These angiogenic factors can then promote the formation of new blood vessels, which can provide the tumor with a supply of nutrients and oxygen, allowing it to grow and spread.

The accumulation of ammonia can also impact the formation of phenylacetate (PA) and phenylacetylglutamine (PAG), as ammonia can interfere with the metabolic pathways involved in the formation of these molecules. Ammonia can compete with phenylalanine for the enzymes involved in the formation of PA and PAG, leading to decreased formation of PA and PAG and increased levels of phenylalanine in the body {ref} in line with the levels observed in cancer patients {ref|ref}.

Dr. Max Gerson (1881 – 1959)  claimed that cancer cells contained too much sodium and too little potassium suggesting that this sodium-to-potassium imbalance was the underlying factor behind cancer development {ref}. Potentially, ammonia may be displacing potassium from the interior of the cell as well, resulting in lowered respiration and eventually leading to a shift from cellular respiration to glycolysis {ref}.

Cancer cells require high levels of lipid synthesis and uptake to support their continued replication. Highly expressed SREBPs play an important role in lipid reprogramming in a variety of cancers. Ammonia released from glutamine can activate glucose-regulated N-glycosylated SCAP and dissociate from INSIG, leading to the translocation and activation of  SREBP1, thereby promoting adipogenesis and tumor growth. {ref}

Ammonia can trigger the unbinding of copper. Unbound Cu can inhibit the activity of PHD enzymes, either directly or indirectly, leading to decreased hydroxylation and subsequent stabilization of HIF-α even under normoxic conditions. Stabilized HIF-α translocates to the nucleus, where it dimerizes with HIF-β and binds to hypoxia response elements (HREs) in the DNA, activating the transcription of various genes involved in angiogenesis, metabolism, and other adaptive responses to hypoxia.

Ammonia accumulation can cause tissue hypoxia (decreased oxygen availability in tissues) due to the leftward shift in the oxygen-hemoglobin dissociation curve, which reduces oxygen release from hemoglobin. 

Ammonia can inhibit ADH (alcohol dehydrogenase) activity by altering enzyme structure. Reduced activity of isoenzyme class II ADH may affect disorders in retinoic acid biosynthesis, leading to its deficit. Lower ADH III activity may result in depletion of glutathione, and in initiation of oxidative stress, leading to cancer progression. {ref}

Ammonia can contribute to muscle wasting (cachexia) regardless of the cause of its increased levels. There is a direct link between hyperammonemia and increased myostatin expression.

The Mechanisms of Ammonia in Cancer


 Hypothesis: Ammonia is the catalyst of cancer development. Before the Great Oxygenation Event, three billion years ago, there was very little oxygen in the atmosphere. Instead, the atmosphere contained high concentrations of methane and ammonia, both important energy sources for one-celled organisms. In the context of cancer, ammonia and other nitrogenous substances act as signals and energy for cellular growth and division. An increase in the amount of ammonia and a decrease in the body's ability to excrete raises lactic acid and interferes with oxygen uptake. This, in turn, can lead to hypoxia and produce a shift towards glycolysis for energy production.



Research articles and findings that provide evidence for the various ways ammonia is implicated in cancer, including its effects on cell proliferation, metabolism, tumor growth, and immune response.

  • Na+/K+-ATPase can also use NH+4 in place of K+ as a substrate. {ref}
  • Ammonia
  • Ammonia stimulates SCAP/Insig dissociation and SREBP-1 activation to promote lipogenesis and tumour growth {ref} "ammonia as a key activator that stimulates SCAP–Insig dissociation and SREBP-1 activation to promote tumour growth and demonstrates that SCAP is a critical sensor of glutamine, glucose and sterol levels to precisely control lipid synthesis."
  • Glutamine-released ammonia acts as an unprecedented signaling molecule activating lipid production {ref}
  • Ammonia mediates mitochondrial uncoupling and promotes glycolysis via HIF-1 activation in human breast cancer MDA-MB-231 cells {ref}
  • Ammonia production by intestinal bacteria {ref}
  • The ammonium cation is a positively charged polyatomic ion with the chemical formula NH+4 or [NH 4] +. It is formed by the protonation of ammonia ( NH 3).
  • Ammonia promotes the proliferation of bone marrow-derived mesenchymal stem cells by regulating the Akt/mTOR/S6k pathway {ref}
  • AMMONIA AND BLOOD SUGAR. BY A. A. HORVATH {ref}
  • Ammonia can contribute to muscle wasting regardless of the cause of its increased levels. There is a direct link between hyperammonemia and increased myostatin expression ˃ cancer and cachexia.
  • Adaptation of renal ammonia production in the diabetic ketoacidotic rat {ref}
  • THE ROLE OF INSULIN AND GLUCAGON IN MAMMALIAN AMMONIA HOMEOSTASIS. STUDIES WITH AMMONIA-INDUCED OROTIC ACIDURIA IN RATS {ref}
  • Ammonia Drives Dendritic Cells into Dysfunction {ref}
  • Moderate grade hyperammonemia activates lactate dehydrogenase-4 and 6-phosphofructo-2-kinase to support increased lactate turnover in the brain slices {ref}
  • Increased ammonia levels and its association with visceral obesity and insulin resistance {ref}
  • Nitrogen anabolism underlies the importance of glutaminolysis in proliferating cells {ref}
  • Effect of fatty acids on the disposition of ammonia {ref}
  • Effects of ammonia on growth performance, lipid metabolism and cecal microbial community of rabbits {ref}
  • Ammonia Induces Autophagy through Dopamine Receptor D3 and MTOR {ref}
  • Dopamine Receptor Subtypes Differentially Regulate Autophagy {ref}
  • Phenylacetylglutamine May Replace Urea as a Vehicle for Waste Nitrogen Excretion {ref}
  • Microenvironmental Ammonia Enhances T cell Exhaustion in Colorectal Cancer {ref|ref}
  • Ammonia can increase the amount of CD44 on the cell surface
  • Ammonia detoxification promotes CD8+ T cell memory development by urea and citrulline cycles {ref}
  • Psychological Stress Triggers a Hyperammonemia Episode in Patient with Ornithine Transcarbamylase Deficiency {ref}
  • Effect of carbohydrate ingestion on ammonia metabolism during exercise in humans {ref}
  • High ammonia levels lead to fewer T cells and immunotherapy resistance in colorectal cancer {ref | ref}
  • Colon Mucosal Cell Damage by Ammonia in Rats {ref}
  • Ammonia Drives Dendritic Cells into Dysfunction {ref}
  • eUREkA! T cells answer nature’s call {ref}
  • From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy {ref}
  • The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling {ref}
  • Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass {ref} "Cancer cells primarily assimilated ammonia through reductive amination catalyzed by glutamate dehydrogenase (GDH), and secondary reactions enabled other amino acids, such as proline and aspartate, to directly acquire this nitrogen."
  • Glutaminolysis
  • Ammonia: its effects on biological systems, metabolic hormones, and reproduction {ref}
  • Testosterone modulates renal ammonia metabolism {ref}
  • Role of glutamine and its metabolite ammonia in crosstalk of cancer-associated fibroblasts and cancer cells {ref}
  • Ammonium, an antagonist of gamma-aminobutyric acid {ref}
  • Effect of ammonia on brain serotonin metabolism in relation to function in the portacaval shunted rat {ref}
  • "increased brain 5-HT turnover in these animals was positively correlated with the degree of hyperammonemia." {ref}
  • Cancer terminally ill patients with liver metastases were significantly higher to exhibit hyperammonemia in this study. {ref}
  • L-Ornithine Aspartate ± a Rationale for Its Use in Combination with Chemotherapy, Radiation, and Hyperthermia in Oncology {ref}
  • Ammonium Metabolism Enzymes Aid Helicobacter pylori Acid Resistance {ref}
  • Lest We Forget: Ammonia in Encephalopathic Cancer Patients (P1-1.Virtual) {ref}
  • THE INFLUENCE OF PUTREFACTION PRODUCTS ON CELLULAR METABOLISM {ref}
  • Nitrate Reduction to Nitrite, Nitric Oxide and Ammonia by Gut Bacteria under Physiological Conditions {ref}
  • Histamine is an organic nitrogenous compound also classified as an amine (News Medical Life Sciences, 2016a). It is a molecule, which is based on the structure of ammonia and formed by the decarboxylation of an amino acid called histidine. Histamine is a biologically active substance, which is produced as part of a local immune response to induce inflammation. It plays an important role in the gut by regulating physiological functions. It can also act as a chemical messenger or a neurotransmitter, which carries signals from one nerve to another. {ref} The blood levels of histamine in patients with a newly diagnosed solid tumor are nearly three-fold greater than in healthy individuals or noncancerous disease controls. Following surgical removal of the malignancy, the level of histamine remains high for 2 months and then drops to the normal range by 3 months after surgery. Collectively, these findings suggest that histamine synthesis is increased in the presence of a tumor.
  • In hepatic encephalopathy with ammonia as a main pathogenic factor, brain histamine concentration is increased (Lozeva et al., 2003)
  • Histamine in Inflammation by Robin Thurmond
  • Histidine Metabolism and Function "Liver is capable of complete catabolism of histidine by a pathway which requires folic acid for the last step, in which glutamate formiminotransferase converts the intermediate N-formiminoglutamate to glutamate, 5,10 methenyl-tetrahydrofolate, and ammonia"
  • Direct Regulation of Histidine Ammonia-Lyase 2 Gene by Thyroid Hormone in the Developing Adult Intestinal Stem Cells {ref}
  • Hypothyroidism is associated with decreased urea synthesis, which may lead to reduced clearance of ammonia.{ref}
  • Effect of Induction of Histidase on Histidine Metabolism in vivo "results suggest that with low dietary levels of histidine, histidine concentration is the major factor regulating histidine metabolism but with high dietary levels of histidine, histidase content becomes important for catabolism of excess histidine and maintenance of low tissue histidine concentrations."{ref}
  • Histidine ammonia-lyase is an enzyme that in humans is encoded by the HAL gene. It converts histidine into ammonia and urocanic acid. L-histidine is important as a precursor of histamine. Salicylates (aspirin-like compounds) can decrease histidine levels.

  • https://tools.myfooddata.com/nutrient-ranking-tool/Histidine/All/Lowest
  • Protonation Behavior of Histidine during HSF1 Activation by Physiological Acidification {ref}
  • Heat Shock Proteins and HSF1 in Cancer {ref}
  • Evidence of a vicious cycle in glutamine synthesis and breakdown in pathogenesis of hepatic encephalopathy–therapeutic perspectives Milan Holecek {ref}
  • Ammonia increases nitric oxide, free Zn2+, and metallothionein mRNA expression in cultured rat astrocytes {ref}
  • Psychological Stress Triggers a Hyperammonemia Episode in Patient with Ornithine Transcarbamylase Deficiency {ref}
  • The effects of insulin on urinary urea and ammonia production {ref}
  • Ammonia raises tryptophan
  • Ammonia increases the concentration of free ferrous iron in mitochondria and autophagosomes/lysosomes thereby promoting astrocyte senescence {ref}














Histidine ammonia-lyase  (HAL):  converts histidine into ammonia and urocanic acid.

Phenylalanine ammonia-lyase (PAL): catalyzes the conversion of L-phenylalanine to ammonia and trans-cinnamic acid (eliminates ammonia from phenylalanine to form trans-cinnamic acid). Trans-cinnamic acid is a precursor of lignins, flavonoids, and coumarins. PAL is found widely in plants, as well as some bacteria, yeast, and fungi.

The Histidine Ammonia Lyase of Trypanosoma cruzi Is Involved in Acidocalcisome Alkalinization and Is Essential for Survival under Starvation Conditions
https://pubmed.ncbi.nlm.nih.gov/34724827/
"Trypanosoma cruzi, the agent of Chagas disease, accumulates polyphosphate (polyP) and Ca2+ inside acidocalcisomes. The alkalinization of this organelle stimulates polyP hydrolysis and Ca2+ release. Here, we report that histidine ammonia lyase (HAL), an enzyme that catalyzes histidine deamination with production of ammonia (NH3) and urocanate, is responsible for acidocalcisome alkalinization."

Tyrosine ammonia-lyase (TAL)

PAL, HAL, and TAL yield cinnamic acid, urocanic acid, and p-coumaric acid, respectively.

HAL-mediated non-oxidative deamination, yields urocanate that is further converted to N-formiminoglutamate. The latter is either used for the synthesis of 5-formiminotetrahydrofolate (in mammals), or is further degraded to glutamate (in 27 bacteria and some fungi).

Of the natural ammonia-lyase substrates, both histidine and phenylalanine cannot be
produced by human metabolism, whereas tyrosine can be synthesized, but only via selective
hydroxylation of phenylalanine.

Some cancer types, such as melanoma, which have been shown to be sensitive to the restriction of tyrosine.

Ammonia-lyases (act on primary metabolites with often strict substrate preference and lack of requirement for cofactor supplementation) produce benign products such as cinnamate, p-coumarate or urocanate (and trace amounts of ammonia).

Tumor cell proliferation is fuelled largely by the blood-born substrate pool of primary metabolites, which includes all proteinogenic amino acids. Whilst some of these protein building blocks can be obtained through cellular metabolism from other starting materials, many cannot be produced by human metabolic processes and are therefore taken up by proliferating cells.

The suite of amino acids required for growth varies between cell types and is therefore not uniform across different forms of cancer. However, the majority of human cells require nine ‘essential’ amino acids that are sourced from dietary protein and thus depletion of these in the blood plasma is a promising strategy to restrict uncontrolled cell division. Of the natural ammonia-lyase substrates, both histidine and phenylalanine cannot be produced by human metabolism, whereas tyrosine can be synthesized, but only via selective hydroxylation of phenylalanine. However, there are also specific cancer types, such as melanoma, which have been shown to be sensitive to the restriction of tyrosine. As such, the use of these enzymes for the selective removal of an aromatic amino acid provides a means by which tumor progression can be slowed down or halted with minimal effect to non-cancerous resting cells. One such example discloses the use of a more recently discovered HAL to control of cell growth in prostate and ovarian cancer cell lines by removing histidine as a precursor for protein synthesis and histamine production. This work also details the potential of HAL-mediated metabolite depletion as a means of inducing reversible arrest of the cell cycle in normal tissues, thus allowing unaffected tumor cells to be targeted more selectively by anticancer drugs

Fabio Parmeggiani, Nicholas J. Weise, Syed T. Ahmed and Nicholas J. Turner

https://pubmed.ncbi.nlm.nih.gov/2120224/

Effects of histidine load on ammonia, amino acid, and adenine nucleotide concentrations in rats

Glucagon is one of the hormones involved in the induction of HAL {ref}

A lipotrope-dependent increase of histidase and urocanase in the livers of choline-deficient rats and in the reuber H-35 transplanted hepatoma {ref}

Long-Term Effects of Histidine Depletion on Whole-Body Protein Metabolism in Healthy Adults {ref}

Xylooligosaccharide decreases blood ammonia levels in patients with liver cirrhosis {ref}

Polyethylene glycol versus lactulose in the treatment of hepatic encephalopathy: a systematic review and meta-analysis {ref | ref}


L-ornithine and phenylacetate synergistically produce sustained reduction in ammonia and brain water in cirrhotic rats {ref}


AMMONIA-LOWERING STRATEGIES FOR THE TREATMENT OF HEPATIC ENCEPHALOPATHY {ref}



Diabetic patients tend to have altered protein metabolism due to abnormal glucose homeostasis resulting in hyperammonemia. {ref|ref}

Amino Acids Downregulate SIRT4 to Detoxify Ammonia through the Urea Cycle {ref}

"The central ammonia-coordinating role of SIRT4 is further supported by the fact that SIRT4 prevents the differentiation of radial glial cells into astrocytes (45), the functions of which are important for preventing HE (46-49). These findings are consistent with our results indicating that Sirt4 knockout prevented HE induction by CCl4. Moreover, CP-K levels are correlated with ageing (11), suggesting that inefficient ammonia removal associated with aging and may cause degenerative diseases. Elucidation of ammonia toxicity-regulating abilities of SIRT4 may enable its inhibition, leading to enhancement of ammonia detoxification and containment of diseases, such as renal failure, aging, and HE"

The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4 {ref}

mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). Thus, a relationship between mTORC1, SIRT4, and cancer is suggested by our findings.

Ammonia exposure alters the expression of immune-related and antioxidant enzymes-related genes and the gut microbial community of crucian carp (Carassius auratus) {ref}

Excessive ammonia inhalation causes liver damage and dysfunction by altering gene networks associated with oxidative stress and immune function {ref}

Ammonia loading in cell culture systems {ref}




FOXO1 activates glutamine synthetase gene in mouse skeletal muscles through a region downstream of 3=-UTR: possible contribution to ammonia detoxification {ref} (high levels of insulin inhibit FOXOs)

HYPERAMMONEMIA IN UNCONTROLLED DIABETES MELLITUS {ref} (insulin deficiency causes hyperglycemia increasing protein catabolism and ammonia production)


Effect of long-term hyperbaric stress on ammonia metabolism in humans {ref}

Glutaminolysis-ammonia-urea Cycle Axis, Non-alcoholic Fatty Liver Disease Progression and Development of Novel Therapies {ref}

Fatty acid oxidation protects cancer cells from apoptosis by increasing mitochondrial membrane lipids {ref}

Hyperammonemia Post Lung Transplantation: A Review {ref}

Grass Tetany: An Hypothesis Concerning its Relationship with Ammonium Nutrition of Spring Grasses {ref} "An hypothesis suggests that grass tetany is caused by the peculiar growing conditions during early spring resulting in unique compositional characteristics of spring forages. Winter leaching, low soil temperatures, and application of ammonium containing fertilizers make the ammonium ion the principal source of nitrogen available to the plant during this period. Absorption of ammonium by
the plant results in greatly reduced uptake of magnesium and calcium with little effect on potassium and produces high amide concentration in the plant with depletion of carbohydrates. These factors combine in the animal to create a high concentration in the rumen of free ammonia and an increased pH, depletion of the remaining carbohydrate, and a further reduction in the availability of the already low magnesium and calcium. When these factors are expressed, they result in low magnesium
in blood serum and interact to produce hypomagnesemic tetany in the animal. "

Proteome of rare liver cancer sheds new light on basic biology {ref}

"That the tumor is producing ammonia would also explain why some liver treatments (which focus on breaking down ammonia in the gut) have fallen flat, while others have shown promise. “A number of patients came out of comas after their physicians switched from treatments that target gut ammonia to treatments that target ammonia throughout the body,” Simon says. 

The researchers hope their findings may ultimately have an impact on the larger study of cancer biology and ammonia metabolism. It would not be the first time an intent look at a rare cancer bore broadly-applicable fruit. Tumor suppressor genes were initially discovered in rare retinoblastomas; a particular enzyme now implicated in many cancers was first characterized in a rare glioblastoma. The present study’s close look at ammonia metabolism through the lens of a rare cancer could open up as-yet unknown pathways for scientific discovery. 

“Basic research tells us about the pathology of the disease, but it goes both ways,” Simon says. “Disease pathology also teaches us about the basic physiology of the human body, and fibrolamellar may well end up giving us a better understanding of ammonia metabolism itself.” "


Ammonia is added to tobacco (to increase nicotine absorption). People who smoke cigarettes are 15 to 30 times more likely to get lung cancer or die from lung cancer than people who do not smoke.




Ammonia can lead to the unbinding of copper, increasing free copper.

Acid-Induced Downregulation of ASS1 Contributes to the Maintenance of Intracellular pH in Cancer {ref}

Alkalosis can lead to tissue hypoxia (decreased oxygen availability in tissues) due to the leftward shift in the oxygen-hemoglobin dissociation curve, which reduces oxygen release from hemoglobin. 

Diaz-Fontenla, Fernando & Castillo, Marta & Díaz-Gomez, Arantxa & Ibanez Samaniego, Luis & Gancedo, Pilar & Villoria, Juan & Fernández, Pilar & Bañares, Rafael & Garcia-Martinez, Rita. (2017). Refractory Hepatic Encephalopathy and Hypothyroidism: A New Factor in the Ammonia Metabolism. Journal of Clinical and Experimental Hepatology. 7. S47-S49. 10.1016/j.jceh.2017.01.063. 


Cancer thus seems to be a metabolic disruption, and ammonia its catalyst.
Por lo tanto, el cáncer parece ser una alteración metabólica y el amoníaco su catalizador.
Kanker lijkt dus een verstoring van de stofwisseling te zijn en ammoniak de katalysator.
Le cancer apparaît ainsi comme un dérèglement métabolique et l'ammoniac comme son catalyseur.
O câncer, portanto, parece ser uma perturbação metabólica, e a amônia, seu catalisador.
Таким образом, рак, по-видимому, является нарушением обмена веществ, а аммиак — его катализатором.
因此，癌症似乎是一種代謝紊亂，而氨則是其催化劑。
Kræft synes således at være en metabolisk forstyrrelse, og ammoniak dens katalysator.
Cancer verkar alltså vara en metabolisk störning och ammoniak dess katalysator.
Krebs scheint also eine Stoffwechselstörung zu sein und Ammoniak sein Auslöser.
Il cancro sembra quindi essere una perturbazione metabolica e l'ammoniaca il suo catalizzatore.
وهكذا يبدو أن السرطان هو اضطراب استقلابي ، والأمونيا حافز لها.
したがって、癌は代謝の混乱を引き起こし、アンモニアはその触媒であると考えられます。



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