To investigate the mode of action of sc injected intestinal carcinogens, the mutagenicity assay of bile collected from noninbred Sprague-Dawley rats treated sc with carcinogens was conducted in the presence and absence of beta-glucuronidase. The bile samples from rats inoculated with 4-aminobiphenyl were mutagenic for Salmonella typhimurium TA100 only in the presence of beta-glucuronidase ... .
Multistep in vitro/in vivo transformation system was used to test the transforming effect(s) of the human bladder procarcinogen 4-amino-biphenyl (ABP) and two putative proximate carcinogenic metabolites, N-hydroxy-4-aminobiphenyl (N-OH-ABP) and N-hydroxy-4-acetylamino-biphenyl (N-OH-AABP), on a clonally derived nontumorigenic SV40-immortalized human uroepithelial cell line, SV-HUC. SV-HUC were exposed in vitro to concentrations of ABP, N-OH-ABP, or N-OH-AABP that caused a range of cytotoxicity from 5 to 76%. Tumorigenic transformation of SV-HUC, as assessed by the ability of the exposed cells to form carcinomas when inoculated s.c. into athymic nude mice, was achieved after a single exposure to ABP, N-OH-ABP, or N-OH-AABP. ... Forty independent carcinomas generated in athymic nude mice recapitulated diverse cancer phenotypes (including different growth kinetics and histopathological subtypes and grades) represented in clinical bladder cancers. These results demonstrate for the first time the transforming effects of the potent human carcinogen ABP and two of its proximate N-hydroxy metabolites on a prime human target cell type, HUC.
... Here we found that CYP2A13 can metabolically activate 4-aminobiphenyl (ABP) to show genotoxicity by Umu assay. The K(m) and V(max) values for ABP N-hydroxylation by recombinant CYP2A13 in E. coli were 38.5 +/- 0.6 uM and 7.8 +/- 0.0 pmol/min/pmol CYP, respectively. The K(m) and V(max) values by recombinant CYP1A2 were 9.9 +/- 0.9 uM and 39.6 +/- 0.9 pmol/min/pmol CYP, respectively, showing 20-fold higher intrinsic clearance than CYP2A13. In human bladder, CYP2A13 mRNA, but not CYP1A2, is expressed at a relatively high level. Human bladder microsomes showed ABP N-hydroxylase activity (K(m) = 34.9 +/- 4.7 uM and V(max) = 57.5 +/- 1.9 pmol/min/mg protein), although the intrinsic clearance was 5-fold lower than that in human liver microsomes (K(m) = 33.2 +/- 2.0 uM and V(max) = 293.9 +/- 5.8 pmol/min/mg protein). The activity in human bladder microsomes was prominently inhibited by 8-methoxypsoralen, but not by fluvoxamine, anti-CYP1A2 or anti-CYP2A6 antibodies. CYP2S1, which is expressed in human bladder and has relatively high amino acid identities with CYP2As, did not show detectable ABP N-hydroxylase activity. In conclusion, although the enzyme responsible for ABP N-hydroxylation in human bladder microsomes could not be determined, we found that CYP2A13 metabolically activates ABP.
Metabolites of the human carcinogen 4-aminobiphenyl (4-ABP) form hemoglobin (Hb) adducts, which represent a useful biomarker for exposure. However, not every individual responds to a similar degree to 4-ABP exposure, and variations in 4-ABP-Hb adduct formation might be explained by genetic polymorphisms in genes coding for enzymes involved in 4-ABP metabolism. 4-ABP-Hb adducts were measured in blood samples from 57 smoking and 10 non-smoking volunteers. An association was found between cigarette smoking and 4-ABP-Hb adduct levels in smokers (R(2) = 0.5, p<0.001). Subsequently, subjects were genotyped for 12 polymorphisms in seven genes involved in biotransformation reactions. From this selection of polymorphisms, a significant impact was found for the CYP1B1 Leu(432)Val polymorphism (p=0.021), which has been reported to lead to a decrease in enzyme activity. Indeed higher levels of 4-ABP-Hb adducts were observed in homo- and heterozygous carriers of the CYP1B1 (432)Leu as compared to the double CYP1B1 (432)Val genotype. A significant interaction between these CYP1B1 genotypes and the level of exposure was found (p=0.003). Noteworthy, a saturation effect was observed for 4-ABP-Hb adduct formation at high smoking doses limited to carriers of the CYP1B1 (432)Leu allele. No effect of polymorphisms in other genes were found. This ... study ... /suggests/ a crucial role of the CYP1B1 enzyme in 4-ABP metabolism, indicating a protective effect of the CYP1B1 Leu(432)Val polymorphism against the formation of 4-ABP-Hb adduct levels, depending on the smoking dose.
来源:Hazardous Substances Data Bank (HSDB)
代谢
4-氨基联苯已知的人类代谢物包括4-氨基联苯和N-氧化物。
4-aminobiphenyl has known human metabolites that include 4-aminobiphenyl, N-oxide.
IDENTIFICATION AND USE: 4-Biphenylamine (BPA) is a solid. It is used in detection of sulfates, and as carcinogen in cancer research. HUMAN EXPOSURE AND TOXICITY: 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. BPA forms BPA-DNA adducts 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. ANIMAL STUDIES: 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). In BPA- treated mice dose-related neoplasms were angiosarcomas, bladder urothelial carcinomas and hepatocellular neoplasms. The non-neoplastic dose-related lesions were left atrial thrombosis, bladder urothelial hyperplasia, splenic hemosiderosis and splenic erythropoiesis. The incidences of bladder carcinoma and atrial thrombosis were higher in the males and the incidences of hepatocellular neoplasms and angiosarcomas were higher in the females. BPA gave positive results in the mouse bone marrow micronucleus test. BPA produced both frameshift and base pair substitution mutations In Salmonella typhimurium TA-98 and TA-100. ECOTOXICITY STUDIES: The system most sensitive to BPA was D. magna immobilization, followed by development of zebrafish embryos, and inhibition of mammalian cell proliferation.
4-Aminobiphenyl requires metabolic activation in order to exert its toxicity. This is catalyzed by N-hydroxylation via cytochrome P450 1A2, then followed by O-sulfation and O-acetylation by sulfotransferase 1A1 and arylamine N-acetyltransferase 2. The metabolites of 4-aminobiphenyl may form adducts with DNA, inducing mutations. 4-Aminobiphenyl and its metabolites may also cross the placenta and have fetal effects. (A2454, A2455, A2456, A2457)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌性证据
在人类中有充分的致癌性证据。在动物中有充分的致癌性证据。总体评估：第1组：该物质对人类具有致癌性。
Sufficient evidence of carcinogenicity in humans. Sufficient evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 1: The agent is carcinogenic to humans.
The personal use of hair dye products is currently under discussion due to the potentially increased risk of bladder cancer among long-time users described in epidemiological literature. In order to investigate the dermal absorption of aromatic diamines as well as aromatic amines possibly present as contaminants in hair dye formulations, we conducted a biomonitoring study under real-life conditions and calculated kinetics and doses for the urinary excretion. Urine samples of two female subjects were collected for a time period of 48 hr after personal application of a hair dye cream and analyzed for aromatic diamines as well as o-toluidine and 4-aminobiphenyl using highly specific GC/MS-methods. 2,5-Toluylenediamine (2,5-TDA) as active ingredient of hair dyes is rapidly absorbed dermally. After a distribution phase of 12 hr, 2,5-TDA is excreted with a half-time of 8 hr. Excretion was 90% complete within 24 hr after application. The doses of 2,5-TDA excreted within 48 hr were 700 ug for application of a brown-reddish hair dye cream and 1.5 mg for the application of a brown-black hair dye cream. Urinary 4-aminobiphenyl as well as contaminations with other aromatic diamines were not detectable in our study. Due to the artifactual formation of o-toluidine in the presence of high concentrations of urinary 2,5-TDA, our results could not prove an increased internal exposure of humans to carcinogenic amines after personal application of hair dyes.
/MILK/ The potential for 4-aminobiphenyl (4-ABP) to be transferred from circulating blood into the milk of lactating Sprague-Dawley rats was determined. The distribution of 14C-labeled 4-ABP into milk was examined at time intervals of less than 1, 20, 60, 120, 240 and 480 min after iv dose administration. Elimination of radioactivity from blood and milk was determined to be biphasic. The levels of 4-ABP and/or metabolites were lower in milk than in blood at all time points examined. The levels of radioactivity detected in blood declined less rapidly than in milk. That is, the percent of the dose per ml of blood declined from 0.81-0.45, while the percent of the dose per ml of milk declined from 0.38-0.06 during the 8 hr time period. The radioactivity present in milk was partially extractable with ethyl acetate with 43% of the radioactivity being extractable at the earliest time point while only 16% was extractable after 8 hr. The level of radioactivity associated with the protein precipitate of the milk samples increased from 4-21% within 4 hr after treatment.
... A sensitive (32)P-postlabeling method enabled us to study the binding of the environmental carcinogens safrole (600 umol/kg p.o.), 4-aminobiphenyl (800 umol/kg), and benzo(a)pyrene (200 umol/kg) to the DNA of various maternal and fetal tissues after administration of test carcinogens to pregnant ICR mice on day 18 of gestation. The results show that these carcinogens bound to the DNA of maternal and fetal liver, lung, kidney, heart, brain, intestine, skin, maternal uterus, and placenta, with organ-specific quantitative and qualitative differences. It was possible for the first time to analyze DNA adduct patterns in minute amounts of tissue, for example those available from fetal heart. The covalent binding index (umol adducted nucleotides per mol of DNA nucleotides/umol carcinogen administered per g body weight) 24 hr after safrole treatment was estimated for the different organs and ranged from 0.1 to 247 and 0.1 to 5.8 for maternal and fetal DNA, respectively. Covalent binding index values of 0.2 to 13 and 0.1 to 0.3 for maternal and fetal DNA, respectively, were found for 4-aminobiphenyl. Benzo(a)pyrene treatment yielded covalent binding index values of 0.6 to 6.5 and 0.3 to 0.7 for maternal and fetal DNA, respectively. In both maternal and fetal tissues, safrole exhibited preferential binding to liver DNA. 4-Aminobiphenyl bound preferentially to DNA of maternal liver and kidney but showed no preference among fetal tissues. Benzo(a)pyrene exhibited weak tissue preference in both maternal and fetal organs. For all of the compounds studied, the fetal adduct levels were generally lower than the corresponding maternal adduct levels, especially when the level of maternal adduction was high. The major finding was that several carcinogens of diverse structure or their metabolites readily crossed the placenta and gave rise to DNA adducts in fetal organs. ...
Maternal-fetal exchange of a potent tobacco related human carcinogen, 4-aminobiphenyl, was studied in smoking (n= 14) and nonsmoking (n= 38) pregnant women. N-Hydroxy-4-aminobiphenyl, the active metabolite of 4-aminobiphenyl, forms chemical addition products (adducts) with hemoglobin. Levels of 4-aminobiphenyl hemoglobin adducts were measured in maternal fetal paired blood samples obtained from smoking and nonsmoking women during labor and delivery. Carcinogen hemoglobin adducts were detected in all maternal and fetal blood samples. Levels of such adducts were significantly higher (p<0.001) in maternal and fetal blood samples from smokers: the mean 4-aminobiphenyl hemoglobin adduct level was 92 +/- 54 pg/g of hemoglobin in blood samples from fetuses of smokers, and 17 +/- 13 pg/g of hemoglobin in blood samples from fetuses of nonsmokers; the mean maternal 4-aminobiphenyl hemoglobin adduct level was 183 +/- 108 pg/g of hemoglobin in smokers, and 22 +/- 8 pg/g of hemoglobin in nonsmokers. Fetal carcinogen adduct levels were consistently lower than maternal levels: the mean maternal to fetal ratio was 2.4 +/- 1.1 in smokers and 1.9 +/- 0.98 in nonsmokers. Fetal 4-aminobiphenyl hemoglobin adduct levels were strongly associated (correlation coefficient r2= 0.51, p=0.002) with maternal 4-aminobiphenyl hemoglobin adduct levels when paired samples from smoking mothers were analyzed. A measure of third trimester tobacco smoke exposure based on number of cigarettes smoked per day, amount of each cigarette smoked, and depth of inhalation was associated (r2= 0.59, p=0.029) with maternal 4-aminobiphenyl levels but not with fetal 4-aminobiphenyl levels. This study demonstrates that a potent tobacco related carcinogen, 4-aminobiphenyl, or its active metabolite, N-hydroxy-4-aminobiphenyl, crosses the human placenta and binds to fetal hemoglobin in concentrations that are significantly higher in smokers than in nonsmokers.
硼酸酯作为有机合成中的关键原材料和中心中间体的应用越来越广泛。从高度丰富且可再生的原料中合成它们仍然很有趣。在这里，我们报告了一种从苯酚合成芳基/杂芳基硼酸酯的有效且一锅法。在该方法中，苯酚首先被硫酰氟活化形成芳基氟磺酸盐，然后与双(频哪醇)二硼发生钯催化的脱氧硼化反应，得到一系列硼酸酯。该方法表现出优异的官能团耐受性，适用于天然产物和现有药物分子的合成。此外，该方案还适用于生物质衍生的酚类的硼化，包括天然存在的和生物活性的化合物。尤其，小鼠乳腺癌细胞中的2 O 2 。
Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
申请人：Vertex Pharmaceuticals Incorporated
公开号：US20150231142A1
公开（公告）日：2015-08-20
The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
(NAPE-PLD) is a membrane-associated zinc enzyme that catalyzes the hydrolysis of N-acylphosphatidylethanolamines (NAPEs) into fatty acid ethanolamides (FAEs). Here, we describe the identification of the first small-molecule NAPE-PLD inhibitor, the quinazoline sulfonamide derivative 2,4-dioxo-N-[4-(4-pyridyl)phenyl]-1H-quinazoline-6-sulfonamide, ARN19874.
Arenesulfonyl Fluoride Synthesis via Copper-Catalyzed Fluorosulfonylation of Arenediazonium Salts
作者：Yongan Liu、Donghai Yu、Yong Guo、Ji-Chang Xiao、Qing-Yun Chen、Chao Liu
DOI：10.1021/acs.orglett.0c00484
日期：2020.3.20
We report herein a general and practical copper-catalyzed fluorosulfonylation reaction of a wide range of abundant arenediazonium salts to smoothly prepare various arenesulfonylfluorides using the 1,4-diazabicyclo[2.2.2]octane-bis(sulfur dioxide) adduct as a convenient sulfonyl source in combination with KHF2 as an ideal fluorine source and without the need for additional oxidants. Interestingly,
Metal‐Free Synthesis of
<i>N</i>
‐Aryl Amides using Organocatalytic Ring‐Opening Aminolysis of Lactones
作者：Wusheng Guo、José Enrique Gómez、Luis Martínez‐Rodríguez、Nuno A. G. Bandeira、Carles Bo、Arjan W. Kleij
DOI：10.1002/cssc.201700415
日期：2017.5.9
Catalytic ring‐opening of bio‐sourced non‐strained lactones with aromatic amines can offer a straightforward, 100 % atom‐economical, and sustainable pathway towards relevant N‐aryl amide scaffolds. Herein, the first general, metal‐free, and highly efficient N‐aryl amide formation is reported from poorly reactive aromatic amines and non‐strained lactones under mild operating conditions using an organic
Phenyl 4-(2-oxopyrrolidin-1-yl)benzenesulfonates and phenyl 4-(2-oxopyrrolidin-1-yl)benzenesulfonamides as new antimicrotubule agents targeting the colchicine-binding site
agents designated as N-phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB–SOs) and phenyl4-(2-oxoimidazolidin-1-yl)benzenesulfonamides (PIB–SAs). Our previous structure-activity relationship studies (SAR) focused on the aromatic ringB of PIB-SOs and PIB-SAs leaving the impact of the phenylimidazolidin-2-one moiety (ring A) on the binding to the colchicine-bindingsite (C-BS) poorly studied. Therefore
