User:Toxi1234/sandbox
| Identifiers | |
|---|---|
| CAS Number | |
| Chemical and physical data | |
| Formula | C12H11N |
| Density | (20 C) 1.16 g/cm3 |
| Melting point | 53 °C (127 °F) |
| Boiling point | 302 °C (576 °F) |
4-aminobiphenyl
[edit]Introduction
[edit]4-aminobiphenyl is an aromatic amine, these compounds are considered as importance in the industrial and commercial industry. These compounds are used as intermediates in numerous synthesis of organic compounds. Exposure to this aryl-amine occurs in chemical dyes, the rubber industries and form cigarette smoke.[1] It enters the body via the skin, via the dyes and it also enters the body via inhalation of the cigarette smoke. 4-aminobiphenyl is suspected causes bladder cancer in humans and dogs and DNA damage.[2] Due to its carcinogenic effects, 4-aminobiphenyl was seized in commercial production in the United States since the 1950s.[3]
Structure and reactivity
[edit]4-aminobiphenyl is an aromatic amine which is a toxic compound. At room temperature the compound is a solid,with a light brown color, in the form of a crystal it has a colorless to yellow-brown color. If 4-aminobiphenyl is in contact with are it turns purple, this is due to a oxidation reaction. Furthermore the compound is insoluble in water. [4]
Reactivity
4-aminobiphenyl is a weak base, this is due to the fact that it contains an amine group, which are known for their basic character. Besides, a weak basic character 4-aminobiphenyl is incompatible with acids and acid anhydrides. If a reaction with hydrochloric acid and sulfuric acid takes place, a salt will be formed. furthermore it will undergo an oxidation reaction with strong oxidation reagents [5]
Synthesis
[edit]
4-aminobiphenyl can be synthesized in various ways, with a different starting material. An example of a synthesis is shown below.
Diphosphorus tetraiodide (P2I4) is used to cleave nitrogen-nitrogen bonds, giving an amine as product. In the synthesis of 4-aminophenyl an 4-azidobiphenyl is used as starting material. P2I4 is heated in dry benzene for several hours and the reaction is worked up with water. The azide subsituent is cleaved and the desired amine is formed.[6]
Mechanism of Action
[edit]General Mechanism
[edit]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 isozyme. (see metabolism) The final products of this metabolism are arylnitrenium ions which form DNA adducts leading to changes in the protein synthesis. 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 reduction of 4-aminobiphenyl to a hydronitroxide)[7]
4-ABP leading to mutation in p53 gene
[edit]A known mechanism in which 4-ABP causes bladder cancer is a mutation in the p53 gene, which are seen in thirty to sixty percent of bladder cancer cases. The p53 gene codes for the tumor suppressor p53 proteins, and therefore a mutation in this gene can lead to formation of tumors. Like previously mentioned the 4-ABP will be metabolized by a cytochrome P450 isozyme in the liver which leads to electrophilic derivatives that can form DNA adducts. The DNA adducts inhibit protein synthesis. In the case of the mutation of the p53 gene in bladder cancer the formed adduct is dG-C8-4-ABP. The mechanism of formation of this adduct can be seen in the figure. Five p53 hotspots are known for bladder cancer. These are three CpG sites 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.[8]
Metabolism
[edit]Cytochrome P450 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 UGT, UDP-glucuronosyltransferase 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 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 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.[9]
Toxicity
[edit]Acute Toxicity
[edit]Toxic fumes arise from this compound when heated to decomposition.[10] Excessive inhalation exposure of 4-aminobiphenyl may induce headache, lethargy, cyanosis and burning sensations mainly in the urinary tract.[11]
Chronic Toxicity
[edit]4-aminobiphenyl is a known human carcinogen, specifically to the tissues involving the urinary system. This compound may cause cancer to the bladder, ureter and renal pelvis. Out of 171 workers in a plant manufacturing 4-aminobiphenyl, 11% of them developed bladder tumors.[10] Tumors appeared on subjects which were exposed by 4-aminobiphenyl in a range of duration from 1.5 to 19 years. The compound forms adducts with DNA in human urothelial mucosa and bladder tumor tissues. Levels of 4-aminobiphenyl-hemoglobin adducts in smokers of blond and black tobacco were found to be proportional to bladder cancer risk.[10]
Toxicity on Animals
[edit]| Organism[12] | Test Type | Route of Ingestion | Dose | Area of Effect |
|---|---|---|---|---|
| Dog | LDLO | Oral | 25 mg/kg | Blood |
| Mouse | LD50 | Oral | 205 mg/kg | - |
| Mouse | LDLO | Intraperitoneal | 250 mg/kg | Lungs and Thorax |
| Rabbit | LD50 | Oral | 690 mg/kg | - |
| Rabbit | LD50 | Oral | 690 mg/kg | Lungs and Thorax |
| Rat | LD50 | Oral | 500 mg/kg | Lungs and Thorax |
Effects on Animals
[edit]Repeated oral administration of a 25% 4-aminobiphenyl solution in olive oil led rabbits to weight loss, anemia, decrease in the number of lymphocytes, increase of granulocytes or the rod neutrophilic granulocyte and to a pronounced hematuria or hemoglobinuria. The oral LD50 of purified 4-aminobiphenyl for rats are 500 mg/kg body weight and for rabbits are 690 mg/kg body weight. The animals also showed increased respiratory rate, lacrimation, loss of appetite, weight loss, muscle weakness, difficulty in breathing and finally coma. Slight irritation in the gastrointestinal tract as well as pneumonia, and changes to the myocardium was observed.[11][13]
In contact with tissues, 4-aminobiphenyl can be metabolized to aryl nitrenium, which creates adducts with DNA.[14] A linear correlation was found between adduct levels and the occurence of liver tumors in female mice by comparing DNA adducts and tumorigenesis. However, the relationship was non-linear in the bladders of male mice. Seven rabbits were given 4-aminobiphenyl orally, and the treatment was continued until the start of the final illness. The treatment resulted in the rabbits having bladder carcinomas, which was observed after four years of treatment. Four young adult female mongrel dogs were given 4-aminobiphenyl orally. The treatment resulted in bladder carcinomas observed in all the subjects after 21 to 34 months. The first occurrence of tumors appeared after a dose of 87.5-144.0 g per dog was given (8.2-14.1 g/kg body weight).[15]
References
[edit]- ^ Radomski, J.L. (1979). "THE PRIMARY AROMATICAMINES: THEIR BIOLOGICAL PROPERTIES AND STRUCTUREACTIVITY RELATIONSHIPS". Annual Reviews. 19: 129–157. Retrieved 2018-03-22.
- ^ Babu, S.R. (1996). "Glucuronide Conjugates of +Aminobiphenyl and Its Hydroxy Metabolites". Elsevier Science. 51: 1679–1685, . Retrieved 2018-03-22.
{{cite journal}}: CS1 maint: extra punctuation (link) - ^ Koss, L.G. (1969). "Further cytologic and histologic studies of bladder lesions in workers exposed to para-aminodiphenyl: progress report". Journal of National Cancer Institute. 43 (1): 233–243. Retrieved 2018-03-21.
- ^ "4‑Aminobiphenyl". Retrieved 2018-03-22.
- ^ "4‑Aminobiphenyl". Retrieved 2018-03-22.
- ^ Suzuki, H. "Reactions of Aromatic Azido, Azo, Azoxy and Hydrazo Compounds with Diphosphorus Tetraiodide". The Chemical Society of Japan. 58: 1861-1862.
- ^ Murate, M. (1 April 2001). "Mechanism of oxidative DNA damage induced by carcinogenic 4-aminobiphenyl". Free Radical Biology & Medicine. 30 (7): 765-773. Retrieved 22 March 2018.
- ^ Feng, Z. (2002-10-01). "4-Aminobiphenyl is a major etiological agent of human bladder cancer: evidence from its DNA binding spectrum in human p53 gene". Carcinogenesis. 23 (10): 1721–1727. doi:10.1093/carcin/23.10.1721. ISSN 0143-3334.
- ^ Babu, S. R.; Lakshmi, V. M.; Huang, G. P.; Zenser, T. V.; Davis, B. B. (1996-06-28). "Glucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolites. pH stability and synthesis by human and dog liver". Biochemical Pharmacology. 51 (12): 1679–1685. ISSN 0006-2952. PMID 8687483.
- ^ a b c "4‑Aminobiphenyl" (PDF). Retrieved 2018-03-14.
- ^ a b the german pdf
- ^ "4-Biphenylamine". Retrieved 2018-03-21.
- ^ Tao, Chen (2005). "4‐Aminobiphenyl induces liver DNA adducts in both neonatal and adult mice but induces liver mutations only in neonatal mice". International Journal of Cancer. 117 (2): 182–187. Retrieved 2018-03-14.
- ^ Murata, Mariko (2001). "Mechanism of oxidative DNA damage induced by carcinogenic 4-aminobiphenyl". Free Radical Biology and Medicine. 30 (7). Elsevier: 765–773. Retrieved 2018-03-21.
- ^ "4‑Aminobiphenyl". Retrieved 2018-03-14.