Sodium phenylbutyrate, sold under the brand name Buphenyl among others, is a salt of an aromatic fatty acid,
4-phenylbutyrate
Sodium phenylbutyrate, sold under the brand name Buphenyl among others, is a salt of an aromatic fatty acid, 4-phenylbutyrate (4-PBA) or 4-phenylbutyric acid. The compound is used to treat urea cycle disorders, because its metabolites offer an ...
(4-PBA) or 4-phenylbutyric acid.
[ The compound is used to treat ]urea cycle disorder
The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic.
The urea cycle converts highly ...
s, because its metabolites offer an alternative pathway to the urea cycle to allow excretion of excess nitrogen.
Sodium phenylbutyrate is also a histone deacetylase inhibitor
Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that enzyme inhibitor, inhibit histone deacetylases. Since acetylation of histones, deacetylation of histones produces transcriptionally silenced heterochromatin ...
and chemical chaperone, leading respectively to research into its use as an anti-cancer agent
This is a list of antineoplastic agents used to treat cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the ...
and in protein misfolding
In medicine, proteinopathy ( 'pref''. protein -pathy 'suff''. disease proteinopathies ''pl''.; proteinopathic ''adj''), or proteopathy, protein conformational disorder, or protein misfolding disease, is a class of diseases in which certain prote ...
diseases such as cystic fibrosis
Cystic fibrosis (CF) is a genetic disorder inherited in an autosomal recessive manner that impairs the normal clearance of Sputum, mucus from the lungs, which facilitates the colonization and infection of the lungs by bacteria, notably ''Staphy ...
.
Structure and properties
Sodium phenylbutyrate is a sodium salt of an aromatic fatty acid, made up of an aromatic ring
In organic chemistry, aromaticity is a chemical property describing the way in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibits a stabilization stronger than would be expected from conjugation alone. The e ...
and butyric acid
Butyric acid (; from , meaning "butter"), also known under the systematic name butanoic acid, is a straight-chain alkyl carboxylic acid with the chemical formula . It is an oily, colorless liquid with an unpleasant odor. Isobutyric acid (2-met ...
. The chemical name for sodium phenylbutyrate is 4-phenylbutyric acid, sodium salt. It forms water-soluble off-white crystals.
Uses
Medical uses
Sodium phenylbutyrate is taken orally or by nasogastric intubation
Nasogastric intubation is a medical process involving the insertion of a plastic tube (nasogastric tube or NG tube) through the nose, down the esophagus, and down into the stomach. Orogastric intubation is a similar process involving the insertio ...
as a tablet or powder, and tastes very salty and bitter. It treats urea cycle disorder
The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic.
The urea cycle converts highly ...
s, genetic diseases in which nitrogen waste builds up in the blood plasma as ammonia
Ammonia is an inorganic chemical compound of nitrogen and hydrogen with the chemical formula, formula . A Binary compounds of hydrogen, stable binary hydride and the simplest pnictogen hydride, ammonia is a colourless gas with a distinctive pu ...
glutamine (a state called hyperammonemia
Hyperammonemia, or high ammonia levels, is a metabolic disturbance characterised by an excess of ammonia in the blood. Severe hyperammonemia is a dangerous condition that may lead to brain injury and death. It may be primary or secondary.
Ammoni ...
) due to deficiences in the enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
s carbamoyl phosphate synthetase I
Carbamoyl phosphate synthetase I (CPS I) is a ligase enzyme located in the mitochondria involved in the production of urea. Carbamoyl phosphate synthetase I (CPS1 or CPSI) transfers an ammonia molecule to a molecule of bicarbonate that has been ...
, ornithine transcarbamylase
Ornithine transcarbamylase (OTC) (also called ornithine carbamoyltransferase) is an enzyme () that catalyzes the reaction between carbamoyl phosphate (CP) and ornithine (Orn) to form citrulline (Cit) and phosphate (Pi). There are two classes of O ...
, or argininosuccinic acid synthetase
Argininosuccinate synthase or synthetase (ASS; ) is an enzyme that catalyzes the synthesis of argininosuccinate from citrulline and aspartate. In humans, argininosuccinate synthase is encoded by the '' ASS gene'' located on chromosome 9.
ASS ...
. Uncontrolled, this causes intellectual impairment and early death. Sodium phenylbutyrate metabolites allows the kidneys to excrete excess nitrogen in place of urea
Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...
, and coupled with dialysis, amino acid supplements and a protein-restricted diet, children born with urea cycle disorders can usually survive beyond 12 months. Patients may need treatment for all their life. The treatment was introduced by researchers in the 1990s, and approved by the U.S. Food and Drugs Administration (FDA) in April 1996.
Adverse effects
Nearly of women may experience an adverse effect
An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term compli ...
of amenorrhea
Amenorrhea or amenorrhoea is the absence of a menstrual period in a female organism who has reached reproductive age. Physiological states of amenorrhoea are most commonly seen during pregnancy and lactation (breastfeeding). In humans, it is wher ...
or menstrual dysfunction. Appetite loss is seen in 4% of patients. Body odor due to metabolization of phenylbutyrate affects 3% of patients, and 3% experience unpleasant tastes. Gastrointestinal symptoms and mostly mild indications of neurotoxicity
Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...
are also seen in less than 2% of patients, among several other reported adverse effects. Administration during pregnancy is not recommended because sodium phenylbutyrate treatment could mimic maternal phenylketonuria
Phenylketonuria (PKU) is an inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine. Untreated PKU can lead to intellectual disability, seizures, behavioral problems, and mental disorders. It may also r ...
due to the production of phenylalanine, potentially causing fetal brain damage.[
]
Research
Urea cycle disorders
Sodium phenylbutyrate administration was discovered to lead to an alternative nitrogen disposal pathway by Dr. Saul Brusilow
Saul (; , ; , ; ) was a monarch of ancient Israel and Judah and, according to the Hebrew Bible and Old Testament, the first king of the United Monarchy, a polity of uncertain historicity. His reign, traditionally placed in the late eleventh cen ...
, Mark Batshaw
Mark Levitt Batshaw (born 19 September 1945) is a Canadian-born physician, medical researcher and academic administrator. He was a professor in the department of pediatrics and an associate dean at the George Washington University School of Medici ...
and colleagues at the Johns Hopkins School of Medicine
The Johns Hopkins University School of Medicine (JHUSOM) is the medical school of Johns Hopkins University, a private research university in Baltimore, Maryland. Established in 1893 following the construction of the Johns Hopkins Hospital, th ...
in the early 1980s, due to some serendipitous discoveries. They had studied ketoacid
In organic chemistry, keto acids or ketoacids (also called oxo acids or oxoacids) are organic compounds that contain a carboxylic acid group () and a ketone group ().Franz Dietrich Klingler, Wolfgang Ebertz "Oxocarboxylic Acids" in Ullmann's En ...
therapy for another inborn error of metabolism
Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrat ...
, citrullinemia
Citrullinemia is an autosomal recessive urea cycle disorder that causes ammonia and other toxic substances to accumulate in the blood.Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. .
Two for ...
, in the late 1970s and they noticed that arginine
Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...
treatment led to an increase of nitrogen in the urine and a drop in ammonia in the blood. The researchers spoke to Norman Radin
Norman S. Radin was a neurochemist who, along with Jim Shayman, developed eliglustat, a drug for treating Gaucher's disease. Born in New York City, he received a B.S. in 1941 and Ph.D. in 1949 from Columbia University, later becoming an associat ...
about this finding, and he remembered a 1914 article on using sodium benzoate
Sodium benzoate also known as benzoate of soda is the sodium salt of benzoic acid, widely used as a food preservative (with an E number of E211) and a pickling agent. It appears as a white crystalline chemical with the formula C6H5COONa.
Pro ...
to reduce urea excretion. Another 1919 article had used sodium phenylacetate, and so the researchers treated five patients with hyperammonemia with benzoate and phenylacetate and published a report in ''Science
Science is a systematic discipline that builds and organises knowledge in the form of testable hypotheses and predictions about the universe. Modern science is typically divided into twoor threemajor branches: the natural sciences, which stu ...
''.[ In 1982 and 1984, the researchers published on using benzoate and arginine for urea cycle disorders in the '']NEJM
''The New England Journal of Medicine'' (''NEJM'') is a weekly medical journal published by the Massachusetts Medical Society. Founded in 1812, the journal is among the most prestigious peer-reviewed medical journals. Its 2023 impact factor was ...
''.[ Use of sodium phenylbutyrate was introduced in the early 1990s, as it lacks the odor of phenylacetate.][
]
Chemical chaperone
In cystic fibrosis
Cystic fibrosis (CF) is a genetic disorder inherited in an autosomal recessive manner that impairs the normal clearance of Sputum, mucus from the lungs, which facilitates the colonization and infection of the lungs by bacteria, notably ''Staphy ...
, a point mutation in the Cystic Fibrosis Transmembrane Conductance Regulator
Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene.
Geneticist Lap-Chee Tsui and his team identified the ''CFTR'' gene in 1989 as the gene lin ...
protein, ΔF508-CFTR, causes it to be unstable and misfold, hence trapped in the endoplasmic reticulum and unable to reach the cell membrane. This lack of CFTR in the cell membrane leads to disrupted chloride transport and the symptoms of cystic fibrosis. Sodium phenylbutyrate can act as a chemical chaperone, stabilising the mutant CFTR in the endoplasmic reticulum and allowing it to reach the cell surface.
Histone deacetylase inhibitor
Deriving from its activity as a histone deacetylase inhibitor
Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that enzyme inhibitor, inhibit histone deacetylases. Since acetylation of histones, deacetylation of histones produces transcriptionally silenced heterochromatin ...
, sodium phenylbutyrate is under investigation for use as a potential differentiation-inducing agent in malignant glioma
A glioma is a type of primary tumor that starts in the glial cells of the brain or spinal cord. They are malignant but some are extremely slow to develop. Gliomas comprise about 30% of all brain and central nervous system tumors and 80% of ...
and acute myeloid leukaemia
Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may inclu ...
,[ and also for the treatment of some ]sickle-cell
Sickle cell disease (SCD), also simply called sickle cell, is a group of inherited haemoglobin-related blood disorders. The most common type is known as sickle cell anemia. Sickle cell anemia results in an abnormality in the oxygen-carrying p ...
disorders as an alternative to hydroxycarbamide
Hydroxycarbamide, also known as hydroxyurea, is an antimetabolite medication used in sickle-cell disease, essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera, and cervical cancer. In sickle-cell disease it increases f ...
due to it inducing expression of fetal hemoglobin
Fetal hemoglobin, or foetal haemoglobin (also hemoglobin F, HbF, or α2γ2) is the main oxygen carrier protein in the human fetus. HemoglobinF is found in fetal red blood cells, and is involved in transporting oxygen from the mother's bloodstream ...
to replace missing adult hemoglobin. While small-scale investigation is proceeding, there is to date no published data to support the use of the compound in the clinical treatment of cancer, and it remains under limited investigation. Sodium phenylbutyrate is also being studied as a therapeutic option for the treatment of Huntington's disease.
Other
Phenylbutyrate has been associated with longer lifespans in ''Drosophila
''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...
''.
University of Colorado researchers Curt Freed and Wenbo Zhou demonstrated that phenylbutyrate stops the progression of Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
in mice by turning on a gene called DJ-1 that can protect dopaminergic
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.
Dopaminergic pathways, Dopaminergic brain pathways facil ...
neurons in the midbrain
The midbrain or mesencephalon is the uppermost portion of the brainstem connecting the diencephalon and cerebrum with the pons. It consists of the cerebral peduncles, tegmentum, and tectum.
It is functionally associated with vision, hearing, mo ...
from dying. they plan on testing phenylbutyrate for the treatment of Parkinson's disease in humans.
Pharmacology
Phenylbutyrate is a prodrug
A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...
. In the human body it is first converted to phenylbutyryl-CoA and then metabolized
Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
by mitochondrial beta-oxidation
In biochemistry and metabolism, beta oxidation (also β-oxidation) is the Catabolism, catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl ...
, mainly in the liver and kidneys, to the active form, phenylacetate. Phenylacetate conjugates with glutamine to phenylacetylglutamine, which is eliminated with the urine. It contains the same amount of nitrogen as urea, which makes it an alternative to urea for excreting nitrogen.
Sodium phenylbutyrate taken by mouth can be detected in the blood within fifteen minutes, and reaches peak concentration in the bloodstream within an hour. It is metabolized into phenylacetate within half an hour.
References
{{Portal bar , Medicine
CYP2D6 inhibitors
Orphan drugs
Prodrugs
Organic sodium salts
Nitrogen cycle
Histone deacetylase inhibitors
Phenyl alkanoic acids