Gebruiker:Tox1234/Kladblok
4-aminobiphenyl[bewerken | brontekst bewerken]
Introduction[bewerken | brontekst bewerken]
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. 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.
Structure and reactivity[bewerken | brontekst bewerken]
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. 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
Synthesis[bewerken | brontekst bewerken]
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.
Mechanism of Action[bewerken | brontekst bewerken]
General Mechanism[bewerken | brontekst bewerken]
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)
4-ABP leading to mutation in p53 gene[bewerken | brontekst bewerken]
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.
Toxicity[bewerken | brontekst bewerken]
Acute Toxicity[bewerken | brontekst bewerken]
Acute inhalation exposure induces the occurrence of headache, lethargy, cyanosis and burning sensations mainly in the urinary tract.
Chronic Toxicity[bewerken | brontekst bewerken]
4-aminobiphenyl (BPA) is a known human carcinogen. It is an occupational bladder carcinogen and may cause cancer of the ureters and renal pelves. Eleven percent of 171 workers in a plant manufacturing BPA developed bladder tumors. Tumors appeared 5 to 19 years after initial exposure, which ranged in duration from 1.25 to 10 years. The compound forms adducts with DNA in normal human urothelial mucosa and bladder tumor tissues. Levels of BPA-hemoglobin adducts in smokers of blond (flue-cured) and black (air-cured) tobacco have been found to be proportional to bladder cancer risk. Risk of bladder cancer due to exposure to occupational carcinogens is elevated in genetically determined slow acetylators.[1]
Effects on Animals[bewerken | brontekst bewerken]
Repeated oral administration of a 25% 4-aminobiphenyl solution in olive oil led in rabbits to weight loss, anemia, decrease in the number of lymphocytes, increase of granulocyte or the rod neutrophilic granulocyte and to a pronounced hematuria or hemoglobinuria.
The oral LD 50 of purified 4-aminobiphenyl is for the rat 500 mg / kg body weight and for the rabbit 690 mg / kg body weight. The animals 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 hepatosis, nephrotic changes, pneumonia, and changes of the myocardium was observed (kw A .; Deichmann et al. 1947). The unique dermal application of 100 μ mol 4-aminobiphenyl / kg (16.9 mg / kg) led to methemoglobin formation in male C57BL / 6J mice (CYP1A2 (+ / +), wild-type). Two hours after treatment, the methemoglobin content was about 35%, seven and 24 hours later, the proportion was only slightly increased compared to baseline. In CYP1A2 ( - / -) - Knockout mice the methemoglobin content was statistically significantly higher compared to the wild-type animals with about 42% and also took more slowly again.
A comparison between DNA adducts and tumorigenesis indicated a linear correlation between adduct levels and the incidence of liver tumors in female mice. In the bladders of male mice, however, the relationship was markedly nonlinear. Seven rabbits were given BPA orally, and the treatment was continued until the onset of the final illness. Bladder carcinomas were observed in three rabbits, the earliest after four years of treatment. Four young adult female mongrel dogs were given BPA orally. Bladder carcinomas were observed in all four dogs after 21- 34 months. The total dose until first appearance of tumors was 87.5-144.0 g per dog (8.2-14.1 g/kg bw). [2]