4-Aminobiphenyl (4-APB) is an organic compound with the formula C₆H₅C₆H₄NH₂. It is an

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen Hydrogen is the chemical element wi ...

derivative of

biphenyl Biphenyl (also known as diphenyl, phenylbenzene, 1,1′-biphenyl, lemonene or BP) is an organic compound that forms colorless crystals. Particularly in older literature, compounds containing the functional group consisting of biphenyl less one ...

. It is a colorless solid, although aged samples can appear colored. 4-Aminobiphenyl was commonly used in the past as a rubber antioxidant and an intermediate for dyes. Exposure to this

aryl In organic chemistry, an aryl is any functional group or substituent derived from an aromaticity, aromatic ring, usually an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization, and "Ar ...

can happen through contact with chemical dyes and from inhalation of cigarette smoke. Researches showed that 4-aminobiphenyl is responsible for bladder

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

in humans and dogs by damaging DNA. Due to its carcinogenic effects, commercial production of 4-aminobiphenyl ceased in the United States in the 1950s.

Synthesis and reactivity

Like other

aniline Aniline is an organic compound with the formula C6 H5 NH2. Consisting of a phenyl group attached to an amino group, aniline is the simplest aromatic amine. It is an industrially significant commodity chemical, as well as a versatile starti ...

derivatives, 4-aminobiphenyl is weakly basic. It is prepared by reduction of 4-nitrobiphenyl, which, together with the 2-nitro derivatives, is obtained by

nitration In organic chemistry, nitration is a general class of chemical processes for the introduction of a nitro group into an organic compound. The term also is applied incorrectly to the different process of forming nitrate esters between alcohols an ...

of biphenyl. Another reaction to synthesize 4-aminobiphenyl can be obtained by using 4-azidobiphenyl. This can be done by reacting 4-azidobiphenyl with diphosphorus tetraiodide (P₂I₄), which can cleave the nitrogen-nitrogen bond. This reaction is done in benzene and later on, water is added to promote the formation of amine. Toxi1234

Mechanism of action

General mechanism

4-Aminobiphenyl causes DNA damage, which is thought to be mediated by formation of DNA adducts. In this process, 4-aminobiphenyl is oxidized in the liver giving the ''N''-hydroxy derivative (4-aminobiphenyl-(NHOH)) by a

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

isozyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...

. The final products of this metabolism are aryl nitrenium ions which form DNA adducts. During this process reactive oxygen species might also be produced and lead to oxidative DNA damage which might also play a role in the carcinogenesis. (N-hydroxy derivative causes oxidative DNA damage dramatically enhanced by NADH which leads to oxidation of 4-aminobiphenyl to a hydronitroxide radical). A linear correlation was found between adduct levels and the occurrence of liver tumors in female mice by comparing DNA adducts and

tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...

4-ABP leading to mutation in p53 gene

One mechanism by which 4-ABP causes bladder cancer is a mutation in the

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

gene, which are seen in thirty to sixty percent of bladder cancer cases. The p53 gene codes for the tumor suppressor p53 proteins. A mutation in this gene can lead to formation of tumors. Five p53 hotspots are known for bladder cancer. These are three

CpG site The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...

s that are common hotspots in several human cancers, which are on codons 175, 248 and 273. The other two codons are 280 and 285 do not have CpG sites. These sites are unique hotspots for mutation in bladder cancer and other urinary tract cancers, which chemistry is not yet fully understood. Acetylation reactions

Metabolism process in humans

Cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

1A2 oxidizes 4-aminobiphenyl to ''N''-hydroxy-4-aminobiphenyl. Following ''O''-acetylation, the latter can form DNA adducts. ''O''-Acetylation reactions are catalyzed by NAT, N-acetyltransferase; and UDP-glucuronosyltransferase (UGT) enzymes. Two different enzymes can catalyze this reaction, NAT1 and NAT2. These enzymes can also ''N''-acetylate 4-aminobiphenyl. ''N''-Acetylated products are difficult to oxidize and because of this acetylation is considered a detoxification step for aromatic amines.

Glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gl ...

also represents a major metabolic pathway for carcinogenic aromatic amines. A certain human UGT catalyzes the formation of the ''N''- glucuronide of 4-aminobiphenyl. Glucuronidation results in inactivation and excretion, therefore N-glucuronidation also competes with N-oxidation.4-aminobiphenyl is proposed to initiate bladder cancer by a mechanism involving hepatic N-oxidation and subsequent N-glucuronidation. The N-hydroxy aryl amine N-glucuronide conjugate is thought to be excreted from the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

and to build up in the bladder lumen. N-glucuronides of 4-aminobiphenyl and N-hydroxy-4-aminobiphenyl can be hydrolyzed by acidic urine to their corresponding arylamines, they can in turn enter the bladder epithelium and undergo further metabolism by peroxidation and/or O-acetylation to form DNA adducts.

Toxicity

Human toxicity

Toxic fumes arise from this compound when heated to decomposition. Excessive inhalation exposure of 4-aminobiphenyl may induce acute toxicity such as headache,

lethargy Lethargy is a state of tiredness, sleepiness, weariness, fatigue, sluggishness or lack of energy. It can be accompanied by depression, decreased motivation, or apathy. Lethargy can be a normal response to inadequate sleep, overexertion, overwo ...

, cyanosis and burning sensations mainly in the urinary tract. 4-Aminobiphenyl is a human carcinogen, specifically to the tissues involving the urinary system, i.e., the bladder, ureter, and renal pelvis. In one study, out of 171 workers in a plant manufacturing 4-aminobiphenyl, 11% of them developed bladder tumors. Tumors appeared on subjects which were exposed by 4-aminobiphenyl in a range of duration from 1.5 to 19 years. The compound can be metabolized by humans which the product may form adducts with DNA in human

urothelial Transitional epithelium also known as urothelium is a type of stratified epithelium. Transitional epithelium is a type of tissue that changes shape in response to stretching (stretchable epithelium). The transitional epithelium usually appears ...

mucosa and bladder tumor tissues. Levels of these adducts in smokers of blond and black tobacco were found to be proportional to bladder cancer risk.

Animal toxicity

The (dogs, oral) is 25 mg/kg. The oral LD₅₀ for rats are 500 mg/kg body weight and for rabbits are 690 mg/kg body weight. Repeated oral administration of a 25% 4-aminobiphenyl solution in olive oil led rabbits to weight loss,

anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...

, decrease in the number of lymphocytes, increase of

granulocytes Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They ha ...

or the rod neutrophilic granulocyte and to a pronounced

hematuria Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. “Gross hematuria” occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable w ...

hemoglobinuria Hemoglobinuria is a condition in which the oxygen transport protein hemoglobin is found in abnormally high concentrations in the urine. The condition is caused by excessive intravascular hemolysis, in which large numbers of red blood cells (RBCs) ...

References

{{DEFAULTSORT:Aminobiphenyl, 4- Anilines IARC Group 1 carcinogens Hazardous air pollutants Biphenyls