| Reference | [1]. Cell Biol Int. 2009 Dec;33(12):1280-6. doi: 10.1016/j.cellbi.2009.08.015. Epub 2009 Sep 11.<br />
N-Nitrosopiperidine and N-Nitrosodibutylamine induce apoptosis in HepG2 cells via the caspase dependent pathway.<br />
García A(1), Morales P, Rafter J, Haza AI.<br />
Author information: (1)Departamento de Nutrición, Bromatología y Tecnología de los Alimentos, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain.<br />
The human hepatoma cell line (HepG2) exhibited a dose and time-dependent apoptotic response following treatment with N-Nitrosopiperidine (NPIP) and N-Nitrosodibutylamine (NDBA), two recognized human carcinogens. Our results showed a significant apoptotic cell death (95%) after 24h treatment with NDBA (3.5 mM), whereas it was necessary to use high doses of NPIP (45 mM) to obtain a similar percentage of apoptotic cells (86%). In addition, both extrinsic (caspase-8) and intrinsic pathway (caspase-9) could be implicated in the N-Nitrosamines-induced apoptosis. This study also addresses the role of reactive oxygen species (ROS) as intermediates for apoptosis signaling. A significant increase in ROS levels was observed after NPIP treatment, whereas NDBA did not induce ROS. However, N-acetylcysteine (NAC) did not block NPIP-induced apoptosis. All these findings suggest that NPIP and NDBA induce apoptosis in HepG2 cells via a pathway that involves caspases but not ROS.<br />
DOI: 10.1016/j.cellbi.2009.08.015 PMID: 19748591 [Indexed for MEDLINE]<br />
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[2]. Carcinogenesis. 1982;3(7):777-80. doi: 10.1093/carcin/3.7.777.<br />
Fluoro-substituted N-nitrosamines. 3. Microsomal metabolism of N-nitrosodibutylamine and of fluorinated analogs.<br />
Janzowski C, Gottfried J, Eisenbrand G, Preussman R.<br />
In vitro metabolism of N-nitrosodibutylamine (NDBA) and of three fluorinated analogs, N-nitroso-4,4,4-trifluorobutyl-butylamine (NDBA-F3), N-nitroso-bis(4,4,4-trifluorobutyl)-amine (NDBA-F6) AND N-nitroso-bis(2,2,3,3,4,4,4-hepafluorobutyl)amine (NDBA-F14) was investigated with rat liver microsomes. To elucidate differences in metabolism caused by fluorination, aldehydes, nitrite and unchanged nitrosamines were determined. NDBA, NDBA–F3 and NDBA-F6 were dealkylated and to a smaller extent also denitrosated. Dealkylation at the fluorinated butyl groups was reduced in comparison to the unfluorinated butyl groups. NDBA-F14 was practically unmetabolized by microsomal enzymes in vitro.<br />
DOI: 10.1093/carcin/3.7.777 PMID: 7116573 [Indexed for MEDLINE]<br />
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[3]. J Appl Toxicol. 2008 May;28(4):455-65. doi: 10.1002/jat.1295.<br />
Induction of apoptosis and reactive oxygen species production by N-nitrosopiperidine and N-nitrosodibutylamine in human leukemia cells.<br />
García A(1), Morales P, Arranz N, Delgado E, Rafter J, Haza AI.<br />
Author information: (1)Departamento de Nutrición, Bromatología y Tecnología de los Alimentos, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain.<br />
N-nitrosopiperidine (NPIP) and N-nitrosodibutylamine (NDBA) belong to a group of N-nitrosamines that are widely distributed in foodstuffs and the occupational environment. In the present study, the human promyelocytic leukemia cell line HL-60, was used to characterize the apoptotic effects of N-nitrosamines, and to examine the production of reactive oxygen species (ROS). Apoptotic cells were identified by (i) chromatin condensation (ii) flow cytometry analysis and (iii) poly(ADP-ribose) polymerase (PARP) cleavage. NPIP and NDBA induced morphological changes consistent with apoptotic events in HL-60 cells. Flow cytometry analysis showed that both N-nitrosamines induced apoptotic cell death in a concentration and time dependent-manner. It was observed that NDBA was stronger than NPIP, since it induced a significant apoptotic cell death after 18 h starting from a concentration of 2 mm, whereas NPIP was effective at 10 mm. Furthermore, PARP was markedly cleaved with 0.5 mm of NDBA and 5 mm of NPIP after treatments for 3 and 18 h, respectively. Finally, the ROS level was found to be elevated after 0.5 h of treatment with both N-nitrosamines. Antioxidant N-acetylcysteine (NAC) completely inhibited the ROS production induced by NPIP and NDBA. However, this action seems not to be associated with the apoptosis because NAC did not block N-nitrosamines-induced apoptosis. The data demonstrate that NPIP and NDBA induce apoptosis and ROS production in HL-60 cells.<br />
DOI: 10.1002/jat.1295 PMID: 17929238 [Indexed for MEDLINE]<br />
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[4]. Environ Sci Pollut Res Int. 2020 Aug;27(23):29143-29155. doi: 10.1007/s11356-020-09040-4. Epub 2020 May 19.<br />
Ultrasonic degradation of nitrosodipropylamine (NDPA) and nitrosodibutylamine (NDBA) in water.<br />
Yang Y(1), Zheng Z(1), Zhang D(1), Zhou C(2), Zhang X(3).<br />
Author information: (1)School of Environment and Architecture, University of Shanghai for Science and Technology, Shanghai, 200093, China. (2)Shanghai Municipal Planning & Design Institute Co., Ltd., Shanghai, 200031, China. (3)School of Environment and Architecture, University of Shanghai for Science and Technology, Shanghai, 200093, China. [email protected].<br />
Nitrosodipropylamine (NDPA) and nitrosodibutylamine (NDBA), two highly toxics and carcinogenic disinfection by-products, cannot be efficiently removed by conventional water treatment processes, while the ultrasound treatment was developed as a promising alternative. In this work, nitrosodipropylamine (NDPA) and nitrosodibutylamine (NDBA) are degraded by ultrasound treatment. Greater than 99% of NDPA and NDBA mixing solution could be decomposed within 60 min at neutral pH under optimal ultrasound power and frequency settings of 100 W and 600 kHz, respectively. Free radical reactions (OH•) played a significant role and the reaction sites were predominately at the bubble interface. The degradation of both NDPA and NDBA exhibited pseudo-first-order degradation kinetics, and the rate constant kapp was influenced by a number of factors including ultrasonic frequency, power, initial concentration, initial pH, various anions and cations frequently present in drinking water, hydroxyl radical scavengers, and water matrices, especially the promoting effect of various anions and cations and water matrices. The results of this study suggest the potential for ultrasound treatment as a method for removing NAms from water.<br />
DOI: 10.1007/s11356-020-09040-4 PMID: 32424764 [Indexed for MEDLINE]<br />
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[5]. Toxicology. 1989 Dec 1;59(2):195-209. doi: 10.1016/0300-483x(89)90057-7.<br />
Investigations on organ-specific metabolism and genotoxic effects of the urinary bladder carcinogen N-nitrosobutyl-3-carboxypropylamine (BCPN) and its analogs N-nitrosodibutylamine (NDBA) and N-nitrosobutyl-4-hydroxybutylamine (4-OH-NDBA).<br />
Janzowski C(1), Jacob D, Henn I, Zankl H, Poole-Zobel BL, Eisenbrand G.<br />
Author information: (1)Department of Food Chemistry and Environmental Toxicology, University of Kaiserslautern, F.R.G.<br />
N-Nitrosodibutylamine (NDBA) and its omega-oxidized metabolites N-nitrosobutyl-4-hydroxybutylamine (4-OH-NDBA) and N-nitrosobutyl-3-carboxypropylamine (BCPN) are potent urinary bladder carcinogens. To study putative organ specific activation of BCPN, its alpha-oxidation by liver and urinary bladder microsomal fractions was investigated in comparison to NDBA and 4-OH-NDBA. Additionally, induction of DNA single strand breaks (SSB) was monitored in hepatocytes and in a human lymphoblastoid cell line (Namalva) in the presence and absence of external metabolic activation, including N-nitroso-t-butyl-n-butylamine as a negative control. BCPN was alpha-hydroxylated and dealkylated at both alkyl chains in small rates (about 1 nmol x mg protein-1 x 60 min-1) by microsomes from rat liver and pig urinary bladder epithelium. NDBA and 4-OH-NDBA were dealkylated at similarly low rates by pig urinary bladder microsomes, in strong contrast to the high debutylation rates observed for rat liver microsomes. Correspondingly, SSB induction by NDBA and 4-OH-NDBA was observed in Namalva cells with NDBA and 4-OH-NDBA in the presence of PB-induced rat liver microsomes but not with urinary bladder microsomes or without external activation. BCPN did not induce DNA-damage in Namalva cells (with or without external activation) or in rat hepatocytes. Significant induction of sister chromatid exchanges (SCEs) and micronuclei, however, was observed in Namalva cells after incubation with NDBA and BCPN. Our data suggest activation of BCPN via alpha-oxidation in the urinary bladder, even though activation rate in-vitro is so low that a positive response is not detectable by several short-term tests.<br />
DOI: 10.1016/0300-483x(89)90057-7 PMID: 2588266 [Indexed for MEDLINE]
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