The aromatic fatty acid 4-phenylbutyrate (4-PBA) is the precursor of sodium phenylbutyrate. It is used to treat conditions associated with the urea cycle because its metabolites provide an alternative to that route. This might allow for the removal of excess nitrogen.
Sodium phenylbutyrate has been investigated as a possible treatment for cancer and other protein-misfolding illnesses including cystic fibrosis due to its ability to inhibit histone deacetylase and function as a chemical chaperone.
Characteristics of orderliness and individuality
In its chemical makeup, sodium phenylbutyrate has an aromatic ring connected to butyric acid. Aromatic fatty acid sodium salt. The sodium salt of 4-phenylbutanoic acid has the chemical name phenylbutyrate of sodium. The result is a white, water-soluble crystal.
The salty and unpleasant taste of sodium phenylbutyrate tablets or powder is an unwanted side effect whether the medication is administered orally or via a nasogastric tube. It is used to address issues with the urea cycle that lead to excess nitrogen waste (in the form of ammonia glutamine in the blood plasma) (a state called hyperammonemia). Insufficient levels of the enzymes carbamoyl phosphate synthetase I, ornithine transcarbamylase, or argininosuccinic acid synthetase lead to this condition. If left untreated, it may cause significant delays in growth or even death. Dialysis, amino acid supplements, and a low-protein diet greatly increase the chances of survival for infants born with urea cycle abnormalities. Sodium phenylbutyrate metabolites may help the kidneys excrete excess nitrogen without the need for urea production. Patients may need ongoing medical care for the remainder of their lives. The therapy was developed by scientists in the 1990s and received FDA approval in the 2000s. This April marked the beginning of operations for what would become the Food and Drug Administration (FDA).
Consequences: positive and negative
Amenorrhea is only one of several potential consequences among the 25% of women who have menstrual disturbances. Four per cent of patients say they aren’t as hungry as usual. There is a correlation between phenylbutyrate metabolism and an unpleasant body odour in 3% of patients and an unpleasant taste in the same percentage of patients. Constipation and moderate to severe neurotoxicity are only two of the numerous side effects that have been documented. Treatment with sodium phenylbutyrate should be avoided during pregnancy because it has the potential to cause harm to the fetus’s developing brain by simulating the effects of maternal phenylketonuria caused by phenylalanine production.
- Pathologies are caused by a malfunction in the urea cycle. In the early 1980s, a team of researchers led by Dr Saul Brusilow and included Mark Batshaw at the Johns Hopkins University School of Medicine made the accidental discovery of sodium phenylbutyrate. Chance discoveries paved the route for this advancement. Ketoacid treatment for citrullinemia was first discovered in the late 1970s, and it was shown that the administration of arginine increased nitrogen excreted in the urine while decreasing blood ammonia levels. The use of ketoacids as a therapy for citrullinemia was studied, and this was the outcome. This happened in the ’70s. When Norman Radin heard the team’s results, he recalled reading about the use of sodium benzoate to decrease urea excretion in a 1914 paper. Since another study employing sodium phenylacetate was published in 1919, the researchers decided to treat five patients with hyperammonemia using benzoate and phenylacetate and publish their findings in the journal Science. Study findings on the efficacy of benzoate and arginine in treating urea cycle illnesses were reported in the NEJM in 1982 and 1984, respectively. Since phenylacetate gives off a foul odour, the usage of sodium phenylbutyrate surged in the early 1990s.
- Some kind of chemical buffering agent. The point mutation that causes cystic fibrosis creates a misfolded and unstable version of a protein called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). This prevents the protein from reaching the cell membrane and instead keeps it in the endoplasmic reticulum, where it can’t be broken down. An absence of CFTR in the cell membrane disrupts chloride transport, a defining feature of cystic fibrosis. Sodium phenylbutyrate may have a role in the body as a chemical ‘chaperone’. In doing so, it aids in the endoplasmic reticulum-to-cell-surface trafficking of the mutant CFTR.
- Proteins that inhibit histone deacetylase (HDAC) are enzymes that prevent histones from being acetylated. In malignant glioma and acute myeloid leukaemia, sodium phenylbutyrate is being researched as a potential differentiation-inducing medication due to its ability to inhibit histone deacetylase. Sodium phenylbutyrate is being explored as an alternative to hydroxycarbamide for the treatment of certain sickle-cell illnesses due to its ability to promote the expression of fetal haemoglobin to replace lacking adult haemoglobin. There is no published evidence to support employing the chemical in the therapeutic treatment of cancer, despite the fact that small-scale research is currently being conducted. Sodium phenylbutyrate is now in the research phase as a potential therapeutic medication for Huntington’s disease.
- Phenylbutyrate has been found to extend the lives of drosophila fruit flies. Dr Curt Freed and Wenbo Zhou of the University of Colorado discovered that oral administration of phenylbutyrate may halt the progression of Parkinson’s disease in rats. They did this by activating the DJ-1 gene, which protects dopaminergic neurons in the midbrain from dying. Researchers want to begin testing phenylbutyrate on human subjects for Parkinson’s disease by July 2011.
- The metabolites of phenylbutyrate are responsible for the loss of nitrogen in the environment. One example of a prodrug is phenylbutyrate. The liver and kidneys are responsible for converting phenylbutyrate-CoA to phenylacetate through mitochondrial beta-oxidation.  When glutamine is conjugated with phenylacetate in the urine, phenylacetylglutamine is the end product. Due to its similar nitrogen content to urea, it may be used as a direct replacement in nitrogen removal. When taken orally, a 5-gram dose of pure PBA may be detected in the bloodstream within 15 minutes and peak levels in the blood and circulation can be achieved within an hour. In around 30 minutes, the metabolic process changes into phenylacetate.
Simona LeVey did her degree in psychology at Tel Aviv University. She is interested in mental health, wellness, and lifestyle.
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