Alkilanilinlerin Toksik Etkileri

Year 2014, Issue: 1, 31 - 46, 01.01.2014

Pınar Erkekoğlu

Abstract

Mesane kanseri erkeklerde en yaygın görülen üçüncü kanserdir. Pekçok bileşiğe maruziyet mesane kanseri ile ilişkilendirilmektedir ve alkilanilinler bu tip kansere en çok neden olabileceği düşünülen kimyasallardır. İnsanlar alkilanilinlere sigara içme ve kalıcı saç boyaları ile sürekli olarak maruz kalmaktadır. İnsanlarda alkilanilin maruziyeti hemoglobin katım ürünlerinin varlığı ile belirlenmektedir. Hemoglobin katım ürünlerinin oluşumunun kemiricilerde mesane kanseri ve de karaciğer, nazal kavite ve subkütan doku kanserlerine neden olduğundan şüphelenilmektedir. Bunun yanında, alkilanilinlerin in vivo olarak DNA katım ürünlerinin oluşmasına neden oldukları ve DNA katım ürünü oluşumunun metabolik aktivasyonun yan ürünü olarak ortaya çıktığı belirtilmektedir. Bu bileşiklerin ve metabolitlerinin özellikle 3,5-aminofenol mutajenik ve genotoksik etkilerinin olduğu gösterilmiştir. 3,5-dimetilanilininin diğer alkilanilinler içinde en yüksek karsinojenik bağlanma indeksine sahiptir ve kemirgenlerde orta derecede karsinojen olarak sınıflandırılmaktadır. Bu derlemede farklı alikilanilinler ve bunların toksik etkilerinden bahsedilecektir.

Keywords

alkilanilin, monosiklik aromatik amin, 3-etilanilin, 2-etilanilin, 2, 6-dimetilanilin, 3, 5-dimetilanilin

Toxic Effects of Alkylanilines

Abstract

Bladder cancer is the third most common cancer in the world. Exposure to several compounds is related to bladder cancer occurrence and alkylanilines are the most anticipated chemicals that may cause this type of cancer. Humans are ubiquitously exposed to alkylanilines from cigarette smoking and use of permanent hair dyes. Exposure has been documented in humans based on hemoglobin adducts. Hemoglobin adduct formation was suspected to lead bladder cancer as well as cancers of liver, nasal cavity and subcutaneous tissue in rodents. Besides, alkylanilines were shown to cause DNA adducts in vivo and DNA adduct formation is a byproduct of metabolic activation. These compounds and their metabolites particularly 3,5-dimethylaminophenol were also demonstrated to have mutagenic and genotoxic effects. 3,5-dimethylaniline was shown to have the highest carcinogenic binding index CBI among other alkylanilines in mice and was classified as a moderate carcinogen in rodents. This review will focus on different alkylanilines and their toxic effects.

Keywords

alkylaniline, monocyclic aromatic amine, 3-ethylaniline, 2, ethylaniline, 2, 6-dimethylaniline, 3, 5-dimethylaniline

References

• 1. Yardım, N., Mollahaliloğlu, S., Başara, B.B., “Türkiye’de Kanser Durumu ve Uluslararası Göstergeler İle Uyumunun Değerlendirmesi”, Tuncer, A.M. (Ed.) Türkiye’de Kanser Kontrolü, Ankara. (2009), 51.
• 2. Bilir N. “Mesleksel Kanserler” Tuncer, A.M. (Ed.) Türkiye’de Kanser Kontrolü, Ankara. (2009), 181.
• 3. Dünya Sağlık Örgütü, “Dünya Kanser Raporu”. Lyon: Dünya Sağlık Örgütü, (2008), 444.
• 4. 4-aminobiphenyl. http://monographs.iarc.fr/ENG/Monographs/vol100F/mono100F-6. pdf. (07/03/2014).
• 5. Talaska, G.: Aromatic amines and human urinary bladder cancer: Exposure sources and epidemiology. J Environ Sci Health Part C—Environ Carcinogenesis Ecotoxicol Rev 21, 29 (2003).
• 6. Bilir, N., “Tütün ve Kanser İlişkisi, Ülkemiz Açısından Önemi” Tuncer, A.M. (Ed.) Türkiye’de Kanser Kontrolü, Ankara. (2009),171.
• 7. Castelao, J. E., Yuan, J. M., Skipper, P. L., Tannenbaum, S. R., Gago-Dominguez, M., Crowder J. S., Ross, R. K., Yu, M. C.: Gender- and smoking-related bladder cancer risk. J Natl Cancer Inst, 93, 538 (2001)
• 8. Chung, K.T., Fulk, G.E., Egan, M.: Reduction of azo dyes by intestinal anaerobes. Appl Environ Microbiol, 35, 558 (1978)
• 9. Chung, K.T., Cerniglia, C.E.: Mutagenicity of azo dyes: structure-activity relationships. Mutat Res, 277, 201 (1992)
• 10. Chung, K.T., Murdock, C.A., Zhou, Y., Stevens, S.E. Jr., Li, Y.S., Wei, C.I., Fernando, S.Y., Chou, M.W.: Effects of the nitro-group on the mutagenicity and toxicity of some benzamines. Environ Mol Mutagen, 27, 67 (1996)
• 11. Chung, K.T., Kirkovsky, L., Kirkovsky, A., Purcell, W.P.: Review of mutagenicity of monocyclic aromatic amines: quantitative structure-activity relationships. Mutat Res, 387, 1 (1997)
• 12. Skipper, P.L., Kim, M.Y., Sun, H.L.P., Wogan, G. N., Tannenbaum, S.R.: Monocyclic aromatic amines as potential human carcinogens: old is new again. Carcinogenesis, 31, 50 (2010)
• 13. Auerbach, S. S.: NTP Research Concept: Alkylanilines NTP Board of Scientific Counselors Meeting- July 23-24 2009. http://ntp.niehs.nih.gov/ntp/About_NTP/BSC/ 2009/July/ Draft_ResConcept/alkylanilines.pdf (07/03/2014)
• 14. Gan, J., Skipper, P.L., Tannenbaum, S.R.: Oxidation of 2,6-Dimethylaniline by recombinant human cytochrome P450 and human liver microsomes. Chem Res Toxicol, 14, 67 (2001)
• 15. Envirometal Protection Agency (EPA). 2-ethylaniline; 3-ethylaniline; 3,5-dimethylaniline. http://www.epa.gov/hpv/pubs/summaries/ringsact/c16251tl.pdf. (07/03/2014)
• 16. Kadlubar, F.F., Fu, P.P., Jung, H., Shaikh, A.U., Beland, F.A.: The metabolic N-oxidation of carcinogenic arylamines in relation to nitrogen charge density and oxidation potential. Environ Health Perspect, 87, 233 (1990)
• 17. Kadlubar, F.F.: DNA adducts of carcinogenic aromatic amines. IARC Sci Publ, 125, 199, (1994)
• 18. Cui, L., Sun, H.L., Wishnok, J.S., Tannenbaum, S.R., Skipper, P.L.: Identification of adducts formed by reaction of N-acetoxy-3,5-dimethylaniline with DNA. Chem Res Toxicol, 20, 1730 (2007)
• 19. Famulok, M., Boche, G.: Formation of N-(deoxyguanosin-8-yl) aniline in the in vitro reaction of N-acetoxyaniline with deoxyguanosine and DNA. Ange Chem Int Ed Engl, 28, 468 (1989).
• 20. Gonçalves, L.L., Beland, F.A., Marques, M.M.: Synthesis, characterization, and comparative 32P-postlabeling efficiencies of 2,6-dimethylaniline-DNA adducts. Chem Res Toxicol, 14, 165 (2001)
• 21. Jones, C.R., Sabbioni, G.: Identification of DNA adducts using HPLC/MS/MS following in vitro and in vivo experiments with arylamines and nitroarenes. Chem Res Toxicol, 16, 1251 (2003)
• 22. Marques, M.M., Mourato ,L.L., Santos, M.A., Beland, F.A.: Synthesis, characterization, and conformational analysis of DNA adducts from methylated anilines present in tobacco smoke. Chem Res Toxicol, 9, 99 (1996)
• 23. Meier C., Boche G. N-Aryl-O-(-aminoacyl)hydroxylamine: Modellreaktionen mit desoxyguanosin, guanosin und 5’-guanosinmonophosphat zur aktivierung monocyclischer aromatischer amine (z.B. phenacetin) zu ultimaten carcinogenen Chem Ber, 123, 1699, (1990)
• 24. Novak, M., Kahley, M.J., Lin, J., Kennedy, S.A., James T.G.: Involvement of free nitrenium ions, ion pairs, and preassociation trapping in the reactions of ester derivatives of N-arylhydroxylamines and N-arylhydroxamic acids in aqueous solution. J Org Chem, 60, 8294, (1995)
• 25. Fishbein J.C., McClelland R.A.: Azide ion trapping of the intermediate in the Bamberger rearrangement. Lifetime of a free nitrenium ion in aqueous solution J Am Chem Soc, 109, 2824, (1987)
• 26. Eyer, P.: Reactions of oxidatively activated arylamines with thiols: reaction mechanisms and biologic implications. An overview. Environ Health Perspect, 102S, 123 (1994)
• 27. Guliaev, A.B., Hang, B., Singer, B.: Structural insights by molecular Dynamics simulations into specificity of the major human AP endonuclease toward the benzene-derived DNA adduct, pBQ-C. Nucleic Acids Res, 32, 2844, (2004)
• 28. Chao, M.W., Kim, M.Y., Ye, W., Ge, J., Trudel, L.J., Belanger, C.L., Skipper, P.L., Engelward, B.P., Tannenbaum, S.R., Wogan, G.N.: Genotoxicity of 2,6- and 3,5-Dimethylaniline in cultured mammalian cells: The role of reactive oxygen species. Toxicol Sci, 130, 48 (2012)
• 29. Gan, J., Skipper, P.L., Gago-Domingues, M., Arakawa, K., Ross, R.K., Yu, M.C., Tannenbaum, S.R.: Alkylaniline-hemoglobin adducts and risk of non-smoking-related bladder cancer. J Natl Cancer Inst 96, 1425, (2004)
• 30. Material Safety Data Sheet. Section 1: Chemical Product and Company Identification. 2,6-Dimethylaniline MSDS. http://www.sciencelab.com/msds.php?msdsId =9923805. (07/03/2014)
• 31. PAN Pesticides Database. U.S. National Toxicology Program acute toxicity studies for 2,6-Dimethylaniline. http://www.pesticideinfo.org/List_NTPStudies.jsp? Rec_Id=PC37258) (07/03/2014)
• 32. Er kekoglu, P., Chao, M.W., Ye, W., Ge, J., Trudel, L.J., Skipper, P.L., Koçer-Gümüşel, B., Engelward, B.P., Wogan, G.N., Ta nnenbaum, S.R.: Cytoplasmic and nuclear toxicity of 3,5-dimethylaminophenol and potential protection by selenocompounds. Food Chem Tox 72, 98-110, (2014)
• 33. Government of Canada. 1993. Canadian Environmental Protection Act: Priority Substances List Assessment Report – 3,5´-Dimethylaniline. Environmental Health Center, Health Canada, Ottawa, Ontario, Canada, 10 pp. http://www.hc-sc.gc.ca/ewh-semt/ alt_formats/hecs-sesc/pdf/pubs/contaminants/psl1-lsp1/3_5_dimethylaniline/3_5_ dimethylaniline_e.pdf . (01/05/2009)
• 34. Cui L., Sun, H.L., Wishnok, J.S., Tannenbaum, S.R., Skipper, P.L.: Identification of adducts formed by reaction of N-acetoxy-3,5- dimethylaniline with DNA. Chem Res Toxicol, 20, 1730, (2007)
• 35. Chen, P.X., Moldoveanu, S.C.: Mainstream smoke chemical analyses for 2R4F Kentucky reference cigarette. Beiträge zur Tabakforschung Int, 20, 448, (2003)
• 36. Smith, C.J., Dooly, G.L., and Moldoveanu, S.C.: New technique using solid-phase extraction for the analysis of aromatic amines in mainstream cigarette smoke. J Chromatogr A, 991, 99 (2003)
• 37. Pereira, W.E., Rostad, C.E., Garbarino, J.R., and Hult, M.F.: Groundwater contamination by organic bases derived from coal-tar wastes. Environ Toxicol Chem, 2, 283, (1983)
• 38. Xia, K., and Pillar, G. Anthropogenic organic chemicals in biosolids from selected wastewater treatment plants in Georgia and South Carolina. (2003) http://cms.ce.gatech.edu/gwri/ uploads/proceedings/2003/Xia%20and%20Pillar.pdf. (03/ 07/2014)
• 39. Cauchon, D., Krishnan, K.: In vitro and in vivo evaluations of the methaemoglobinaemic potential of xylidine isomers in the rat. J Appl Toxicol, 17, 397, (1997)
• 40. Shardonofsky, S., Krishnan, K.: Characterization of methemoglobinemia induced by 3,5-xylidine in rats. J Toxicol Environ Health, 50, 595, (1997)
• 41. National Toxicology Program (NTP). Chemical Information Profile for Alkylanilines. 2-Ethylaniline; 3-Ethylaniline; 3,5-Dimethylaniline. (2009) http://ntp.niehs.nih.gov/ntp/ noms/Support_Docs/Alkylanilines060809_508.pdf. (07/03/2014)
• 42. Sabbioni, G.: Hemoglobin binding of arylamines and nitroarenes: molecular dosimetry and quantitative structure-activity relationships. Environ Health Perspect, 102S, 61, (1994)
• 43. Bryant, M.S., Vineis, P., Skipper, P.L., Tannenbaum, S.R.: Haemoglobin adducts of aromatic amines in people exposed to cigarette smoke. IARC Sci Publ, 89, 133 (1988)
• 44. Strife, R.J., Mangels, M.L., Skare, J.A.: Separation and analysis of dimethylaniline isomers by supercritical fluid chromatography—Electrospray ionization tandem mass spectrometry. J Chromatogr A, 1216, 6970, (2009)
• 45. Scientific Commiteee on Consumer products (SSCP). Opinion on p-aminophenol COLIPA n° A16. SCCP/0867/05 (2005). http://ec.europa.eu/health/ph_risk/committees/ 04_sccp/ docs/sccp_o_00e.pdf. (07/03/2014)
• 46. Hill A.B., Jefferies P.R., Quistad G.B., Casida J.E.: Dialkylquinoneimine metabolites of chloroacetanilide herbicides induce sister chromatid exchanges in cultured human lymphocytes. Mutat Res, 395, 159, (1997)
• 47. Jefferies P.R., Quistad G.B., Casida J.E. Dialkylquinonimines validated as in vivo metabolites of alachlor, acetochlor, and metolachlor herbicides in rats. Chem Res Toxicol, 11, 353, (1998)
• 48. Slaughter, D.E., Hanzlik, R.P.: Identification of epoxide- and quinone-derived bromobenzene adducts to protein sulfur nucleophiles. Chem Res Toxicol, 4, 349 (1991)
• 49. Hill B.A., Kleiner H.E., Ryan E.A., Dulik D.M., Monks T.J., Lau S.S.: Identification of multiS-substituted conjugates of hydroquinone by HPLC-coulometric electrode array analysis and mass spectrometry. Chem Res Toxicol, 6, 459, (1993)
• 50. Lau S.S., Monks T.J., Everitt J.I., Kleymenova E., Walker C.L.: Carcinogenicity of a nephrotoxic metabolite of the “nongenotoxic” carcinogen hydroquinone. Chem Res Toxicol, 14, 25, (2001)
• 51. Patel S.K., Ma N., Monks T.J., Lau S.S. Changes in gene expression during chemicalinduced nephrocarcinogenicity in the Eker rat. Mol Carcinog, 38, 141, (2003)
• 52. Weber, E.J., Colón, D., Baughman, G.L.: Sediment-associated reactions of aromatic amines. 1. Elucidation of sorption mechanisms. Environ Sci Technol, 35, 2470 (2001)
• 53. Yang M.Y., Lau S.S., Monks T.J.: 2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ)-mediated apoptosis of human promyelocytic leukemia cells is preceded by mitochondrial cytochrome c release in the absence of a decrease in the mitochondrial membrane potential. Toxicol Sci, 86, 92, (2005)
• 54. Yoon H.S., Monks T.J., Walker C.L., Lau S.S.: Transformation of kidney epithelial cells by a quinol thioether via inactivation of the tuberous sclerosis-2 tumor suppressor gene. Mol. Carcinog, 31, 37, (2001)
• 55. Klos C., Koob M., Kramer C., Dekant W.: p-aminophenol nephrotoxicity: Biosynthesis of toxic glutathione conjugates. Toxicol Appl Pharmacol, 115, 98, (1992)
• 56. Martínez-Cabot, A., Morató, A., Messeguer, A.: Synthesis and stability studies of the glutathione and N-acetylcysteine adducts of an iminoquinone reactive intermediate generated in the biotransformation of 3-(N-phenylamino)propane-1,2-diol: implications for toxic oil syndrome. Chem Res Toxicol, 18, 1721,. (2005)
• 57. Towndrow, K.M., Mertens, J.J., Jeong, J.K., Weber, T.J., Monks, T.J., Lau, S.S.: Stressand growth-related gene expression are independent of chemical-induced prostaglandin E(2) synthesis in renal epithelial cells. Chem Res Toxicol, 13, 111, (2000)
• 58. Canadian Environmental Protection Act. Priority Substanstances List Assessment Report. 3,5-Dimethylaniline. Government of Canada. Health and Welfare Canada. Environment Canada. http://www.hc-sc.gc.ca/ewh-semt/alt_formats/hecs-sesc/pdf/pub s/ contaminants/psl1-lsp1/3_5_dimethylaniline/3_5_dimethylaniline-eng.pdf. (07/03/ 2014)
• 59. Chemical Carcinogenesis Research Information System (CCRIS). 3,5-Xylidene. CCRIS Record No. 4742. (1993). http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+ ccris:@ term+@rn+108-69-0. 07/03/ 2014)
• 60. HSDB. 3,5-Xylidine. HSDB No. 2096. (2005) http://toxnet.nlm.nih.gov/cgi-bin/sis/ search/r?dbs+hsdb:@term+@rn+@rel+108-69-0. (07/03/2014)
• 61. Zimmer, D., Mazurek, J., Petzold, G., and Bhuyan, B.K.: Bacterial mutagenicity and mammalian cell DNA damage by several substituted anilines. Mutat Res, 77, 317 (1980)
• 62. Japan Chemical Industry Ecology-Toxicology and Information Centre (JETOC). (1999) JETOC Information Sheet No. 38, Special Issue No. 5. Tokyo, Japan.
• 63. Seiler, J.P.:. Inhibition of testicular DNA synthesis by chemical mutagens and carcinogens. Preliminary results in the validation of a novel short term test. Mutat Res, 46, 305 (1977)
• 64. Skipper, P.L., Trudel, L.J., Kensler, T.W., Groopman, J.D., Egner, P.A., Liberman, R. G., Wogan, G.N., Tannenbaum, S.R.: DNA adduct formation by 2,6-dimethyl-, 3,5-dimethyl, and 3-ethylaniline in vivo in mice. Chem Res Toxicol, 19, 1086 (2004)
• 65. Lutz, W.K.: In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis. Mutat Res, 65, 289 (1979)
• 66. Skipper, P.L., Trudel, L.J., Kensler, T.W., Groopman, J.D., Egner, P.A., Liberman, R.G., Wogan, G.N., Tannenbaum, S.R.: DNA adduct formation by 2,6-dimethyl-, 3,5-dimethyl-, and 3-ethylaniline in vivo in mice. Chem Res Toxicol, 19, 1086 (2006)
• 67. Chao, M.W., Erkekoglu, P., Tseng, C.Y., Ye, W., Trudel, L.J., Skipper, P.L., Tannenbaum, S.R., Wogan, G.N.: Intracellular generation of ROS by 3,5-dimethylaminophenol: persistence, cellular response, and impact of molecular toxicity. Toxicol Sci, 141, 300 (2014)
• 68. Chao, M.W., Erkekoglu, P., Tseng, C.Y., Ye, W., Trudel, L.J., Skipper, P.L., Tannenbaum, S.R., Wogan, G.N. Protective effects of ascorbic acid against the genetic and epigenetic alterations induced by 3,5-dimethylaminophenol in AA8 cells. J Appl Toxicol. (2014) doi: 10.1002/jat.3046 (basımda).