对烷氧基苯酚类物质(p-AOPs)的雌激素活性
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摘要
对烷氧基苯酚(p-AOPs)是一类广泛应用于化工业、制药业、化妆品等领域的苯酚类化合物,其结构与具有雌激素活性的烷基酚类物质相似,但目前对于p-AOPs的雌激素活性尚未见文献报道.本文利用分子对接技术,预测了常见p-AOPs在人雌激素受体α(hERα)激动剂口袋中的结合情况,发现p-AOPs能够很好地与hERα结合,其酚羟基能够与hERα的Glu353和Arg349形成氢键,疏水区域可以与Phe404等疏水氨基酸产生疏水相互作用;通过磷酸对硝基苯酚法对8种p-AOPs的雌激素活性进行分析,发现4-苯氧基苯酚(PhOP)、4-戊氧基苯酚(PeOP)、4-苄氧基苯酚(PBP)具有较强的雌激素活性,其EC_(50)值分别达到9.41×10~(-7)、1.89×10~(-6)和2.68×10~(-6) mol·L~(-1).与典型环境雌激素双酚A(BPA)的雌激素活性相比, PhOP活性明显强于BPA,而PeOP和PBP与BPA接近.通过分析不同烷基碳链长度的p-AOPs的雌激素活性发现,烷基链碳数在1～5个范围内,碳链越长雌激素活性越大.鉴于p-AOPs具有较强雌激素活性,且其广泛应用于与人体密切接触的一些领域,建议进一步加强对这类物质的人体暴露量、内分泌干扰危害和健康风险的研究.
p-Alkoxyphenols(p-AOPs) are a class of phenolic compounds, which are widely used in chemical industry, cosmetics and pharmaceuticals. The structures of p-AOPs are similar to p-alkylphenols, a well-known estrogenic compounds. However, few studies have reported the estrogenic activity of p-AOPs to date. In this study, we predicted the binding affinities of p-AOPs to human estrogen receptor alpha(hERα) by molecular docking and found that p-AOPs could well bind to hERα agonist pocket. Hydrogen bonds formed between the phenolic hydroxyl group of p-AOPs with Glu315 and Arg349 of hERα and hydrophobic interactions of the phenyl ring and alkyl group of p-AOPs with the core hydrophobic moiety provided by the hydrophobic amino acids of hERα pocket are the important feature of the binding. The estrogenic activities of eight p-alkoxyphenols were then analyzed by using hERα coactivator recruiting assay. p-phenoxyphenol(PhOP), p-pentyloxyphenol(PeOP) and p-benzyloxyphenol(PBP) were found to show strong estrogenic activity, of which the EC_(50) values were close to the typical environmental estrogen, bisphenol A(BPA), reaching 9.41×10~(-7), 1.89×10~(-6) and 2.68×10~(-6) mol·L~(-1), respectively. The estrogen activities of p-alkoxyphenols with 1～5 alkyl carbon chains showed the pattern that the longer alkyl chain possessed the higher estrogenic activity. In view that the strong estrogenic activities of p-alkoxyphenols and their widespread uses, further research on their endocrine effects and health risk assessment are needed.
p-Alkoxyphenols(p-AOPs) are a class of phenolic compounds, which are widely used in chemical industry, cosmetics and pharmaceuticals. The structures of p-AOPs are similar to p-alkylphenols, a well-known estrogenic compounds. However, few studies have reported the estrogenic activity of p-AOPs to date. In this study, we predicted the binding affinities of p-AOPs to human estrogen receptor alpha(hERα) by molecular docking and found that p-AOPs could well bind to hERα agonist pocket. Hydrogen bonds formed between the phenolic hydroxyl group of p-AOPs with Glu315 and Arg349 of hERα and hydrophobic interactions of the phenyl ring and alkyl group of p-AOPs with the core hydrophobic moiety provided by the hydrophobic amino acids of hERα pocket are the important feature of the binding. The estrogenic activities of eight p-alkoxyphenols were then analyzed by using hERα coactivator recruiting assay. p-phenoxyphenol(PhOP), p-pentyloxyphenol(PeOP) and p-benzyloxyphenol(PBP) were found to show strong estrogenic activity, of which the EC_(50) values were close to the typical environmental estrogen, bisphenol A(BPA), reaching 9.41×10~(-7), 1.89×10~(-6) and 2.68×10~(-6) mol·L~(-1), respectively. The estrogen activities of p-alkoxyphenols with 1～5 alkyl carbon chains showed the pattern that the longer alkyl chain possessed the higher estrogenic activity. In view that the strong estrogenic activities of p-alkoxyphenols and their widespread uses, further research on their endocrine effects and health risk assessment are needed.
引文
Alonsomagdalena P, Vieira E, Soriano S, et al. 2010. Bisphenol a exposure during pregnancy disrupts glucose homeostasis in mothers and adult male offspring[J]. Environmental Health Perspectives, 118(9):1243-1250
Dsikowitzky L, Str?ter M, Dwiyitno, et al. 2016. First comprehensive screening of lipophilic organic contaminants in surface waters of the megacity Jakarta, Indonesia [J]. Marine Pollution Bulletin, 110(2): 654-664
Durando M, Kass L, Piva J, et al. 2007. Prenatal bisphenol A exposure induces preneoplastic lesions in the mammary gland in Wistar rats [J]. Environmental Health Perspectives, 115(1): 80-86
Ellis D D, Jone C M, Larson R A, et al. 1982. Organic constituents of mutagenic secondary effluents from wastewater treatment plants [J]. Archives of Environmental Contamination & Toxicology, 11(3): 373-382
Gabriel F L, Cyris M, Giger W, et al. 2010. ipso-Substitution: A general biochemical and biodegradation mechanism to cleave α-quaternary alkylphenols and bisphenol A [J]. Chemistry & Biodiversity, 4(9): 2123-2137
Gabriel Frédéric L P, Cyris M, Jonkers N, et al. 2007. Elucidation of the ipso-substitution mechanism for side-chain cleavage of α-quaternary 4-nonylphenols and 4-t-butoxyphenol in sphingobium xenophagum bayram [J]. Applied & Environmental Microbiology, 73(10): 3320
Herbst A L, Ulfelder H, Poskanzer D C. 1999. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women [J]. American Journal of Obstetrics & Gynecology, 181(6): 1574-1575
Hu Y, Zhang Z, Sun L, et al. 2013. The estrogenic effects of benzylparaben at low doses based on uterotrophic assay in immature SD rats[J]. Food & Chemical Toxicology, 53(3):69-74
Hudnall P M. 2000. Hydroquinone [M]. Ullmann′s Encyclopedia of Industrial Chemistry
Jacobson J L, Jacobson S W. 2003. Prenatal exposure to polychlorinated biphenyls and attention at school age [J]. J Pediatr, 143(6): 780-788
焦健, 张照斌, 胡建英,等. 2010. hVDR原核表达及其与重金属镉、铅的结合活性 [J]. 环境科学, 31(10): 2469-2474
Kanayama T, Kobayashi N, Mamiya S, et al. 2005. Organotin compounds promote adipocyte differentiation as agonists of the peroxisome proliferator-activated receptor gamma/retinoid X receptor pathway [J]. Molecular Pharmacology, 12(12): 1036-1047
Kanayama T, Mamiya S, Nishihara T, et al. 2003. Basis of a high-throughput method for nuclear receptor ligands [J]. Journal of Biochemistry, 133(6): 791-797
Keri R, Ho S M, Hunt P A, et al. 2007. An evaluation of evidence for the carcinogenic activity of bisphenol A [J]. Reproductive Toxicology, 24(2): 240-252
Kim Y H, Cha C J, Engesser K H, et al. 2008. Degradation of various alkyl ethers by alkyl ether-degrading Actinobacteria isolated from activated sludge of a mixed wastewater treatment [J]. Chemosphere, 73(9): 1442-1447
Kochukov M Y, Jeng Y J, Watson C S. 2009. Alkylphenol xenoestrogens with varying carbon chain lengths differentially and potently activate signaling and functional responses in GH3/B6/F10 somatomammotropes [J]. Environmental Health Perspectives, 117(5): 723-730
Kohler Hans-Peter E, Gabriel Frédéric L P, Giger W. 2008. ipso-substitution-A novel pathway for microbial metabolism of endocrine-disrupting 4-nonylphenols, 4-alkoxyphenols, and bisphenol A [J]. Chimia International Journal for Chemistry, 62(5): 358-363(356)
李祥军, 周忠良, 顾建华. 2009. 壬基酚对河川沙塘鳢性腺分化和发育影响的研究 [J]. 水产科学, 28(1): 15-19
Lassmann G, P?tsch S. 1995. Structure of transient radicals from cytostatic-active p-alkoxyphenols by continuous-flow EPR [J]. Free Radical Biology & Medicine, 19(5): 533
Lee J W. 2002. Evaluation of the immune response following exposure of mice to bisphenol A: induction of Th1 cytokine and prolactin by BPA exposure in the mouse spleen cells [J]. Archives of Pharmacal Research, 25(6): 946-953
Lee M H, Chung S W, Kang B Y, et al. 2003. Enhanced interleukin-4 production in CD4+ T cells and elevated immunoglobulin E levels in antigen-primed mice by bisphenol A and nonylphenol, endocrine disruptors: involvement of nuclear factor-AT and Ca2+ [J]. Immunology, 109: 76-86
Matafonova G, Christofi N, Batoev V, et al. 2008. Degradation of chlorophenols in aqueous media using UV XeBr excilamp in a flow-through reactor [J]. Chemosphere, 70(6): 1124-1127
Moridani M Y, Moore M, Bartsch R A, et al. 2005. Structural toxicity relationship of 4-alkoxyphenols′ cytotoxicity towards murine B16-F0 melanoma cell line [J]. Journal of Pharmacy & Pharmaceutical Sciences, 8(2): 348-360
Moridani M Y, Siraki A, O′Brien P J. 2003. Quantitative structure toxicity relationships for phenols in isolated rat hepatocytes [J]. Chemico-Biological Interactions, 147(3): 297-307
Murk A J, Rijntjes E, Blaauboer B J, et al. 2013. Mechanism-based testing strategy using in vitro approaches for identification of thyroid hormone disrupting chemicals [J]. Toxicology in Vitro, 27: 1320-1346
Nadal A, Alonso-Magdalena P, Soriano S. 2009. The pancreatic beta-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes [J]. Molecular & Cellular Endocrinology, 304(1): 63-68
Njoo M D, Vodegel R M, Westerhof W. 2000. Depigmentation therapy in vitiligo universalis with topical 4-methoxyphenol and the Q-switched ruby laser [J]. Journal of the American Academy of Dermatology, 42(5): 760
Pir?elová K, Balá? ?, Schultz T W. 1996. Model-based QSAR for ionizable compounds: Toxicity of phenols against Tetrahymena pyriformis [J]. Archives of Environmental Contamination & Toxicology, 30(2): 170-177
Provenchermandeville J, Debnath C, Mandal S K, et al. 2011. Design, synthesis and biological evaluation of estradiol-PEG-linked platinum(II) hybrid molecules: comparative molecular modeling study of three distinct families of hybrids[J]. Steroids, 76(1):94-103
Sun H, Xu X L, Qu J H, et al. 2008. 4-Alkylphenols and related chemicals show similar effect on the function of human and rat estrogen receptor alpha in reporter gene assay [J]. Chemosphere, 71(3): 582-588
Walkowiak J, Wiener J, Fastabend A, et al. 2002. Environmental exposure to polychlorinated biphenyls and quality of the home environment: Effects on psychodevelopment in early childhood [J]. Lancet, 358(9293): 1602-1607
Yannai S. 2003. Dictionary of food compounds with CD-ROM: Additives, flavors, and ingredients[M]. Chapman and Hall/CRC
Yousefi H, Yahyazadeh A, Rufchahi E O Moradi, et al. 2013. Synthesis, spectral properties, biological activity and application of new 4-(benzyloxy)phenol derived azo dyes for polyester fiber dyeing [J]. Journal of Molecular Liquids, 180: 51-58
Zhang Z B, Hu Y, Guo J L, et al. 2017. Fluorene-9-bisphenol is anti-oestrogenic and may cause adverse pregnancy outcomes in mice [J]. Nature Communications, 8: 14585
Zhang Z B, Jia C X, Hu Y, et al. 2012. The estrogenic potential of salicylate esters and their possible risks in foods and cosmetics [J]. Toxicology Letters, 209(2): 146-153
张慧珠. 2014. 内分泌干扰物生物检测研究进展[J]. 环境科学导刊, (33):8-15
Dsikowitzky L, Str?ter M, Dwiyitno, et al. 2016. First comprehensive screening of lipophilic organic contaminants in surface waters of the megacity Jakarta, Indonesia [J]. Marine Pollution Bulletin, 110(2): 654-664
Durando M, Kass L, Piva J, et al. 2007. Prenatal bisphenol A exposure induces preneoplastic lesions in the mammary gland in Wistar rats [J]. Environmental Health Perspectives, 115(1): 80-86
Ellis D D, Jone C M, Larson R A, et al. 1982. Organic constituents of mutagenic secondary effluents from wastewater treatment plants [J]. Archives of Environmental Contamination & Toxicology, 11(3): 373-382
Gabriel F L, Cyris M, Giger W, et al. 2010. ipso-Substitution: A general biochemical and biodegradation mechanism to cleave α-quaternary alkylphenols and bisphenol A [J]. Chemistry & Biodiversity, 4(9): 2123-2137
Gabriel Frédéric L P, Cyris M, Jonkers N, et al. 2007. Elucidation of the ipso-substitution mechanism for side-chain cleavage of α-quaternary 4-nonylphenols and 4-t-butoxyphenol in sphingobium xenophagum bayram [J]. Applied & Environmental Microbiology, 73(10): 3320
Herbst A L, Ulfelder H, Poskanzer D C. 1999. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women [J]. American Journal of Obstetrics & Gynecology, 181(6): 1574-1575
Hu Y, Zhang Z, Sun L, et al. 2013. The estrogenic effects of benzylparaben at low doses based on uterotrophic assay in immature SD rats[J]. Food & Chemical Toxicology, 53(3):69-74
Hudnall P M. 2000. Hydroquinone [M]. Ullmann′s Encyclopedia of Industrial Chemistry
Jacobson J L, Jacobson S W. 2003. Prenatal exposure to polychlorinated biphenyls and attention at school age [J]. J Pediatr, 143(6): 780-788
焦健, 张照斌, 胡建英,等. 2010. hVDR原核表达及其与重金属镉、铅的结合活性 [J]. 环境科学, 31(10): 2469-2474
Kanayama T, Kobayashi N, Mamiya S, et al. 2005. Organotin compounds promote adipocyte differentiation as agonists of the peroxisome proliferator-activated receptor gamma/retinoid X receptor pathway [J]. Molecular Pharmacology, 12(12): 1036-1047
Kanayama T, Mamiya S, Nishihara T, et al. 2003. Basis of a high-throughput method for nuclear receptor ligands [J]. Journal of Biochemistry, 133(6): 791-797
Keri R, Ho S M, Hunt P A, et al. 2007. An evaluation of evidence for the carcinogenic activity of bisphenol A [J]. Reproductive Toxicology, 24(2): 240-252
Kim Y H, Cha C J, Engesser K H, et al. 2008. Degradation of various alkyl ethers by alkyl ether-degrading Actinobacteria isolated from activated sludge of a mixed wastewater treatment [J]. Chemosphere, 73(9): 1442-1447
Kochukov M Y, Jeng Y J, Watson C S. 2009. Alkylphenol xenoestrogens with varying carbon chain lengths differentially and potently activate signaling and functional responses in GH3/B6/F10 somatomammotropes [J]. Environmental Health Perspectives, 117(5): 723-730
Kohler Hans-Peter E, Gabriel Frédéric L P, Giger W. 2008. ipso-substitution-A novel pathway for microbial metabolism of endocrine-disrupting 4-nonylphenols, 4-alkoxyphenols, and bisphenol A [J]. Chimia International Journal for Chemistry, 62(5): 358-363(356)
李祥军, 周忠良, 顾建华. 2009. 壬基酚对河川沙塘鳢性腺分化和发育影响的研究 [J]. 水产科学, 28(1): 15-19
Lassmann G, P?tsch S. 1995. Structure of transient radicals from cytostatic-active p-alkoxyphenols by continuous-flow EPR [J]. Free Radical Biology & Medicine, 19(5): 533
Lee J W. 2002. Evaluation of the immune response following exposure of mice to bisphenol A: induction of Th1 cytokine and prolactin by BPA exposure in the mouse spleen cells [J]. Archives of Pharmacal Research, 25(6): 946-953
Lee M H, Chung S W, Kang B Y, et al. 2003. Enhanced interleukin-4 production in CD4+ T cells and elevated immunoglobulin E levels in antigen-primed mice by bisphenol A and nonylphenol, endocrine disruptors: involvement of nuclear factor-AT and Ca2+ [J]. Immunology, 109: 76-86
Matafonova G, Christofi N, Batoev V, et al. 2008. Degradation of chlorophenols in aqueous media using UV XeBr excilamp in a flow-through reactor [J]. Chemosphere, 70(6): 1124-1127
Moridani M Y, Moore M, Bartsch R A, et al. 2005. Structural toxicity relationship of 4-alkoxyphenols′ cytotoxicity towards murine B16-F0 melanoma cell line [J]. Journal of Pharmacy & Pharmaceutical Sciences, 8(2): 348-360
Moridani M Y, Siraki A, O′Brien P J. 2003. Quantitative structure toxicity relationships for phenols in isolated rat hepatocytes [J]. Chemico-Biological Interactions, 147(3): 297-307
Murk A J, Rijntjes E, Blaauboer B J, et al. 2013. Mechanism-based testing strategy using in vitro approaches for identification of thyroid hormone disrupting chemicals [J]. Toxicology in Vitro, 27: 1320-1346
Nadal A, Alonso-Magdalena P, Soriano S. 2009. The pancreatic beta-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes [J]. Molecular & Cellular Endocrinology, 304(1): 63-68
Njoo M D, Vodegel R M, Westerhof W. 2000. Depigmentation therapy in vitiligo universalis with topical 4-methoxyphenol and the Q-switched ruby laser [J]. Journal of the American Academy of Dermatology, 42(5): 760
Pir?elová K, Balá? ?, Schultz T W. 1996. Model-based QSAR for ionizable compounds: Toxicity of phenols against Tetrahymena pyriformis [J]. Archives of Environmental Contamination & Toxicology, 30(2): 170-177
Provenchermandeville J, Debnath C, Mandal S K, et al. 2011. Design, synthesis and biological evaluation of estradiol-PEG-linked platinum(II) hybrid molecules: comparative molecular modeling study of three distinct families of hybrids[J]. Steroids, 76(1):94-103
Sun H, Xu X L, Qu J H, et al. 2008. 4-Alkylphenols and related chemicals show similar effect on the function of human and rat estrogen receptor alpha in reporter gene assay [J]. Chemosphere, 71(3): 582-588
Walkowiak J, Wiener J, Fastabend A, et al. 2002. Environmental exposure to polychlorinated biphenyls and quality of the home environment: Effects on psychodevelopment in early childhood [J]. Lancet, 358(9293): 1602-1607
Yannai S. 2003. Dictionary of food compounds with CD-ROM: Additives, flavors, and ingredients[M]. Chapman and Hall/CRC
Yousefi H, Yahyazadeh A, Rufchahi E O Moradi, et al. 2013. Synthesis, spectral properties, biological activity and application of new 4-(benzyloxy)phenol derived azo dyes for polyester fiber dyeing [J]. Journal of Molecular Liquids, 180: 51-58
Zhang Z B, Hu Y, Guo J L, et al. 2017. Fluorene-9-bisphenol is anti-oestrogenic and may cause adverse pregnancy outcomes in mice [J]. Nature Communications, 8: 14585
Zhang Z B, Jia C X, Hu Y, et al. 2012. The estrogenic potential of salicylate esters and their possible risks in foods and cosmetics [J]. Toxicology Letters, 209(2): 146-153
张慧珠. 2014. 内分泌干扰物生物检测研究进展[J]. 环境科学导刊, (33):8-15