Health> Vol.5 No.10A, October 2013

Aflatoxins metabolism, effects on epigenetic mechanisms and their role in carcinogenesis

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ABSTRACT

Chronic consumption of aflatoxin-contaminated foods is a global problem in both developing and developed countries especially where there is poor regulation of their levels in foods. In the body, aflatoxins (AFBs) mainly AFB1 are biotransformed to various metabolites especially the active AFB1-exo-8,9-epoxide (AFBO). The AFB, AFBO and other metabolites interact with various biomolecules in the body including nucleic acids such as DNA and RNA and the various metabolic pathways such as protein synthesis, glycolytic pathway and electron transport chain involved in ATP production in body cells. The AFB interacts with DNA to form AFB-DNA adducts causing DNA breakages. The AFB and its metabolites induce the up regulation of nuclear receptors such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR) through gene expression that regulates the metabolizing enzymes such as CYP450 involved in Phase I and Phase II metabolism of xenobiotics. AFB activates these nuclear receptors to produce the metabolizing enzymes. The AFB1 is metabolized in the body by cytochrome P450 (CYP450) enzyme isoforms such as CYP1A2, CYP1A2, CYP3A4/ CYP3A5, and CYP3A7 in fetus, glutathione S-transferase, aflatoxin B1-aldehyde reductase leading to reactive metabolites, some of which can be used as aflatoxin exposure biomarkers. These enzymes are involved in the Phase I and Phase II metabolic reactions of aflatoxins. The CYP1A2 is the principal metabolizer of aflatoxin at low concentrations while the reverse is true for CYP3A4. The accumulation of AFB and its metabolites in the body especially the AFB1-exo-8,9-epoxide depletes the glutathione (GSH) due to the formation of high amounts of epoxides and other reactive oxygen species (ROS). The AFB, AFB1-exo-8,9-epoxide and other metabolites also affect the epigenetic mechanisms including the DNA methylation, histone modifications, maturation of miRNAs as well as the daily formation of single nucleotide polymorphism (SNP) where AFB exposure may facilitate the process and induces G:C to T:A transversions at the third base in codon 249 of TP53 causing p53 mutations reported in hepatocellular carcinoma (HCC). The changes in epigenetic mechanisms lead to either epigenetic inactivation or epigenetic derepression and all these affect the gene expression, cellular differentiation and growth. AFB also through epigenetic mechanisms promotes tumorigenesis, angiogenesis, invasion and metastasis in hepatocellular carcinoma. However, the formation of the small amounts of AFB1 from AFB2 is suspected to cause the carcinogenicity of AFB2 in humans and animals. Chronic aflatoxins exposure leads to formation of reactive AFBO metabolites in the body that could activate and de-activates the various epigenetic mechanisms leading to development of various cancers.

Cite this paper

Bbosa, G. , Kitya, D. , Odda, J. and Ogwal-Okeng, J. (2013) Aflatoxins metabolism, effects on epigenetic mechanisms and their role in carcinogenesis. Health, 5, 14-34. doi: 10.4236/health.2013.510A1003.

References

[1] Bennett, J.W. and Klich, M. (2003) Mycotoxins. Clinical Microbiology Reviews, 16, 497-516.
http://dx.doi.org/10.1128/CMR.16.3.497-516.2003
[2] Bbosa, G.S., David Kitya, D., Lubega, A., Ogwal-Okeng, J., Anokbonggo, W.W. and Kyegombe, D.B. (2013) Review of the biological and health effects of aflatoxins on body organs and body systems: Aflatoxins—Recent advances and future prospects. Intechopen Publisher, 12, 239-265.
[3] Mushtaq, M., Sultana, B., Anwar, F., Khan, M.Z. and Ashrafuzzaman, M. (2012) Occurrence of aflatoxins in selected processed foods from Pakistan. International Journal of Molecular Sciences, 13, 8324-8337.
http://dx.doi.org/10.3390/ijms13078324
[4] Reddy, S.V. and Waliyar, F. (2012) Properties of aflatoxin and its producing fungi: Aflatoxins, 2012.
http://www.icrisat.org/aflatoxin/aflatoxin.asp
[5] Monosson, E. (2012) Biotransformation. National Library of Medicine (NLM): The Encyclopeadia of earth.
http://www.eoearth.org/view/article/150674/
[6] Eaton, L.D., Evan, P.G., Theo, K.B. and Kent, L.K. (1995) Role of cytochrome P4501A2 in chemical carcinogenesis: Implications for human variability in expression and enzyme activity. Pharmacogenetics, 5.
[7] Vondracek, M., Xi, Z., Larsson, P., Baker, V., Mace, K., Pfeifer, A., Tjalve, H., Donato, M.T., Gomez-Lechon, J. and Grafstrom, R.C. (2001) Cytochrome P450 expression and related metabolism in human buccal mucosa. Carcinogenesis, 22, 481-488.
http://dx.doi.org/10.1093/carcin/22.3.481
[8] Dhanasekaran, D., Shanmugapriya, S., Thajuddin, N. and Panneerselvam, A. (2011) Panneerselvam, aflatoxins and aflatoxicosis in human and animals. In: Guevara-Gonzalez, R.G., Ed., Aflatoxins—Biochemistry and Molecular Biology, InTech, 221-254.
[9] Zhang, B.C., Zhu, Y.R., Wang, J.B., Wu, Y., Zhang, Q.N., Qian, G.S., et al. (1997) Oltipraz chemoprevention trial in Qidong, Jiangsu Province, People’s Republic of China. Journal of Cellular Biochemistry, Suppl. 28-29, 166-173.
http://dx.doi.org/10.1002/(SICI)1097-4644(1997)28/29+<166::AID-JCB20>3.0.CO;2-E
[10] Omar, H.E. (2013) Mycotoxins-induced oxidative stress and disease. INTECH, Chapter 3.
[11] Gallagher, E.P., Wienkers, L.C., Stapleton, P.L., Kunze, K.L. and Eaton, D.L. (1994) Bioactivation of aflatoxin B1DNA-expressed cytochromes P4501A2 and P4503A4 in the role of human. Cancer Research, 54, 101-108.
http://cancerres.aacrjournals.org/content/54/1/101.full.pdf
[12] Code, E.L., Crespi, C.L., Penman, B.W., Gonzalez, F.J., Chang, T.K.H. and Waxman, D.J. (1997) Human cytochrome P4502B6 interindividual hepatic expression, substrate specificity, and role in procarcinogen activation. Drug Metabolism and Disposition, 25, 985-993.
[13] Wild, C.P. and Turner, P.C. (2002) The toxicology of aflatoxins as a basis for public health decisions. Mutagenesis, 17, 471-481.
http://mutage.oxfordjournals.org/content/17/6/471.full.pdf
http://dx.doi.org/10.1093/mutage/17.6.471
[14] Gross-Steinmeyer, K. and Eaton, D.L. (2012) Dietary modulation of the biotransformation and genotoxicity of aflatoxin B(1). Toxicology, 299, 69-79.
http://dx.doi.org/10.1016/j.tox.2012.05.016
[15] Wild, C.P., Yin, F., Turner, P.C., Chemin, I., Chapot, B., Mendy, M., Whittle, H., Kirk, G.D. and Hall, A.J. (2000) Environmental and genetic determinants of aflatoxin-albumin adducts in The Gambia. International Journal of Cancer, 86, 1-7.
[16] Lampe, J.W., King, I.B., Li, S., Grate, M.T., Barale, K.V., Chen, C., Feng, Z. and Potte, J.D. (2000) Brassica vegetables increase and apiaceous vegetables decrease cytochrome P450 1A2 activity in humans: Changes in caffeine metabolite ratios in response to controlled vegetable diets. Carcinogenesis, 21, 1157-1162.
http://dx.doi.org/10.1093/carcin/21.6.1157
[17] Farombi, E.O. and Nwaokeafor, I.O. (2005) Anti-oxidant mechanisms of kolaviron: Studies on serum lipoprotein oxidation, metal chelation and oxidative membrane damage in rats. Clinical and Experimental Pharmacology and Physiology, 32, 667-674.
http://dx.doi.org/10.1111/j.0305-1870.2005.04248.x
[18] Ayed-Boussema, I., Pascussi, J., Maurel, P., Bacha, H. and Hassen, W. (2012) Effect of aflatoxin B1 on nuclear receptors PXR, CAR, and AhR and their target cytochromes P450 mRNA expression in primary cultures of human hepatocytes. International Journal of Toxicology, 31, 86-93.
http://ijt.sagepub.com/content/31/1/86.full.pdf
http://dx.doi.org/10.1177/1091581811422453
[19] Drozdzik, A., Kowalczyk, R., Urasińska, E. and Kurzawski, M. (2013) Expression of nuclear receptors (AhR, PXR, CAR) and transcription factor (Nrf2) in human parotid gland. Acta Poloniae Pharmaceutica, 70, 215-219.
[20] Li, H. and Wang, H. (2010) Activation of xenobiotic receptors: Driving into the nucleus. Expert Opinion on Drug Metabolism & Toxicology, 6, 409-428.
http://dx.doi.org/10.1517/17425251003598886
[21] Maglich, J.M., Stoltz, C.M., Goodwin, B., Hawkins-Brown, D., Moore, J.T. and Kliewer, S.A. (2001) Nuclear pregnane X receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Molecular Pharmacology, 62, 638-648.
http://molpharm.aspetjournals.org/content/62/3/638.full.pdf
[22] Pool-Zobela, B., Veeriaha, S. and Bohmer, F.D. (2005) Modulation of xenobiotic metabolising enzymes by anticarcinogens—Focus on glutathione S-transferases and their role as targets of dietary chemoprevention in colorectal carcinogenesis. Mutation Research, 591, 74-92.
http://dx.doi.org/10.1016/j.mrfmmm.2005.04.020
[23] Halliwell, B. (2007) Oxidative stress and cancer: Have we moved forward? Biochemistry Journal, 401, 1-11.
http://dx.doi.org/10.1042/BJ20061131
[24] Verma, R.J. (2004) Aflatoxin cause DNA damage. International Journal of Human Genetics, 4, 231-236.
[25] Murphy, P.A., Hendrich, S., Landgren, C. and Bryant, C.M. (2006) Food mycotoxins: An update. Journal of Food Science, 71, P51-P65.
http://dx.doi.org/10.1111/j.1750-3841.2006.00052.x
[26] Hayes, J.D., Flanagan, J.U. and Jowsey, I.R. (2005) Glutathione transferases. Annual Reviews in Pharmacology and Toxicology, 45, 51-88.
http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095857
[27] Sherrat, P.J. and Hayes, J.D. (2002) Glutathione S-transferases. Enzyme systems that metabolize drugs and other xenobiotics. Cell Biochemistry, 9, 319-352.
http://www.uniroma2.it/didattica/cellbiochem/deposito/Glutathione_S-transferases.pdf
[28] Thomson-Reuters (2013) Glutathione metabolism: Pathway map details. Thomson Reuters.
http://pathwaymaps.com/maps/896/
[29] Ye, Z., Song, H., Higgins, J.P.T., Pharoah, P. and Danesh, J. (2006) Five glutathione S-transferase gene variants in 23,452 cases of lung cancer and 30,397 controls: Metaanalysis of 130 studies. PLoS Medicine, 3, e91.
http://dx.doi.org/10.1371/journal.pmed.0030091
[30] Kensler, T.W., Qian, G., Chen, J. and Groopman, J.D. (2003) Molecular pathway of aflatoxin detoxification: Translational strategies for cancer prevention in liver. Nature Reviews Cancer, 3, 321-329.
http://dx.doi.org/10.1038/nrc1076
[31] Kensler, T.W., Roebuck, B.D., Wogan, G. N. and Groopman, J.D. (2010) Aflatoxin: A 50-year odyssey of mechanistic and translational toxicology. Toxicological Sciences, 120, S28-S48.
http://toxsci.oxfordjournals.org/content/120/suppl_1/S28.full.pdf
[32] Clifford, J.I. and Rees, K.R. (1967) The interaction of aflatoxins with purines and purine nucleosides. Biochemistry Journal, 103, 467-471.
[33] Kiessling, K.H. (1986) Biochemical mechanism of action of mycotoxins. Pure & Applied Chemistry, 58, 327-338.
http://dx.doi.org/10.1351/pac198658020327
[34] Bhat, N.K., Emeh, J.K., Niranjan, B.G. and Avadhani, N.G. (1982) Inhibition of mitochondrial protein synthesis during early stages of aflatoxin b-induced hepatocarcinogenesis. Cancer Research, 42, 1876-1880.
http://cancerres.aacrjournals.org/content/42/5/1876.full.pdf
[35] Qian, G., Wang, F., Tang, L., Massey, M.E., Mitchell, N.J., Su, J., Williams, J.H., Phillips, T.D. and Wang, J. (2013) Integrative toxicopathological evaluation of aflatoxin B1 exposure in f344 rats toxicologic pathology.
http://tpx.sagepub.com/content/early/2013/02/15
/0192623313477256.full.pdf
[36] Riley, R.T. (1998) Mechanistic interactions of mycotoxins: Theoretical consideration. In: Sinha, K.K. and Bhatanagar, D., Eds., Mycotoxins in Agriculture and Food Safety. Marcel Dekker, Inc, Basel, New York, 227-254.
[37] Riley, R.T. and Norred, W. P. (1996) Mechanisms of mycotoxicity. In: Howard, D.H. and Miller, J.D., Eds., The Mycota, Springer, Berlin, 194-195.
[38] Speijers, G.J.A. and Speijers, M.H.M. (2004) Combined toxic effects of mycotoxins. Toxicology Letters, 153, 91-98.
http://dx.doi.org/10.1016/j.toxlet.2004.04.046
[39] Vermeulen, K., Berneman, Z.N. and Bockstaele, D.R.V. (2003) Cell cycle and apoptosis. Cell Proliferation, 36, 165-175.
http://dx.doi.org/10.1046/j.1365-2184.2003.00267.x
[40] Li, Y., Daniel, M. and Tollefsbol, T.O. (2011) Epigenetic regulation of caloric restriction in aging: Metabolism, diet and disease. BMC Medicine, 9, 98.
http://www.biomedcentral.com/content/pdf/1741-7015-9-98.pdf
http://dx.doi.org/10.1186/1741-7015-9-98
[41] Mohammed, A.M. and Metwally, N.S. (2009) Antiaflatoxicogenic activities of some aqeous plant extracts against AFB1 induced renal and cardiac damage. Journal of Pharmacology and Toxicology, 4, 1-16.
http://dx.doi.org/10.3923/jpt.2009.1.16
[42] Chahwan, R., Wontakal, S. and Roa, S. (2011) The multidimensional nature of epigenetic information and its role in disease. Discovery Medicine.
[43] Balogh, P. and Engelmann, P. (2011) Epigenetic factors in transdifferentiation. Transdifferentiation and regenerative medicine, University of Pécs.
http://www.tankonyvtar.hu/hu/tartalom/tamop425/0011_1A_
Transzdifferenciation_en_book/ch01s03.html
[44] Costa, F.F. (2008) Non-coding RNAs, epigenetics and complexity. Gene, 410, 9-17.
http://dx.doi.org/10.1016/j.gene.2007.12.008
[45] Craig, J.M. and Wong, N.C. (2011) Epigenetics: A reference manual. Caister Academic Press.
[46] Day, J.J. and Sweatt, J.D. (2011) Review of epigenetic mechanisms in cognition. Neuron, 70, 813-829.
http://dx.doi.org/10.1016/j.neuron.2011.05.019
[47] Yang, I.V. and Schwartz, D.A. (2012) Epigenetic mechanisms and the development of asthma. Journal of Allergy and Clinical Immunology, 130, 1243-1255.
http://dx.doi.org/10.1016/j.jaci.2012.07.052
[48] You, J.S. and Jones, P.A. (2012) Cancer genetics and epigenetics: Two sides of the same coin? Cancer Cell Review, 22, 9-20.
[49] Kim, G.H., Ryan, J.J., Marsboom, G. and Archer, S.L. (2011) Epigenetic mechanisms of pulmonary hypertension. Pulmonary Circulation, 1, 347-358.
http://www.pulmonarycirculation.org/temp/PulmCirc13347-4509573_123135.pdf
[50] Millan, M.J. (2013) An epigenetic framework for neurondevelopmental disorders: From pathogenesis to potential therapy. Neuropharmacology, 68, 2-82.
http://dx.doi.org/10.1016/j.neuropharm.2012.11.015
[51] Ehrlich, M. (2009) DNA hypomethylation in cancer cells. Epigenomics, 1, 239-259.
http://dx.doi.org/10.2217/epi.09.33
[52] Goodman, J.I. and Counts, J. L. (1993) Hypomethylation of DNA: A possible nongenotoxic mechanism underlying the role of cell proliferation in carcinogenesis. Environmental Health Perspectives, 101, 169-172.
[53] Reddy, M.A. and Natarajan, R. (2011) Epigenetic mechanisms in diabetic vascular complications. Cardiovascular Research. http://dx.doi.org/10.1093/cvr/cvr024
[54] Pogribny, I.P., Rusyn, I. and Beland, F.A. (2008) Epigenetic aspects of genotoxic and non-genotoxic hepatocarcinogenesis studies in rodents. Environmental Molecular Mutagenicity, 49, 9-15.
http://dx.doi.org/10.1002/em.20342
[55] Li, E. (2002) Chromatin modification and epigenetic reprogramming in mammalian development. Nature Reviews Genetics, 3, 662-673.
http://dx.doi.org/10.1038/nrg887
[56] Cosgrove, M.S., Boeke, J.D. and Wolberger, C. (2004) Regulated nucleosome mobility and the histone code. Nature Structural & Molecular Biology, 11, 1037-1043.
http://dx.doi.org/10.1038/nsmb851
[57] Fenley, A.T., Adams, D.A. and Onufriev, A.V. (2010) Charge state of the globular histone core controls stability of the nucleosome. Biophysical Journal, 99, 1577-1585.
http://dx.doi.org/10.1016/j.bpj.2010.06.046
[58] Latham, J.A. and Dent, S.Y.R. (2007) Histone modification choices: Cross-regulation of histone modifications. Nature Structural & Molecular Biology, 14, 1017-1024.
http://dx.doi.org/10.1038/nsmb1307
[59] Ye, J., Ai, X., Eugeni, E.E., Zhang, L., Carpenter, L.R., Jelinek, M.A., Freitas, M.A. and Parthun, M.R. (2005) Histone H4 lysine 91 acetylation a core domain modification associated with chromatin assembly. Molecular Cell, 18, 23-30.
[60] Su, H., Yang, J., Xu, T., Huang, J., Xu, L., Yuan, Y. and Zhuang, S. (2009) MicroRNA-101, down-regulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity. Journal of Cancer Research, 69, 1135. http://dx.doi.org/10.1158/0008-5472.CAN-08-2886
[61] Yokoi, T. and Nakajima, M. (2013) microRNAs as mediators of drug toxicity. Annual Review of Pharmacology and Toxicology, 53, 377-340.
http://dx.doi.org/10.1146/annurev-pharmtox-011112-140250
[62] Ng, I. (2012) Molecular pathogenesis of hepatocellular carcinoma. Hong Kong Journal of Radiology, 15, S23-S28.
[63] Shen, J., Wang, S., Zhang, Y., Kappil, M.A., Wu, H., Kibriya, M.G., et al. (2012) Genome-wide aberrant DNA methylation of microRNA host genes in hepatocellular carcinoma. Epigenetics, 7, 1230-1237.
http://dx.doi.org/10.4161/epi.22140
[64] Adam, F. (2005) microRNA: A revolution in gene expression. The Journal of Young Investigators.
[65] Park, U.S., Su, J.J., Ban, K.C., Qin, L., Lee, E.H. and Lee, Y.I. (2000) Mutations in the p53 tumor suppressor gene in tree shrew hepatocellular carcinoma associated with hepatitis B virus infection and intake of aflatoxin B1. Gene, 251, 73-80.
http://dx.doi.org/10.1016/S0378-1119(00)00183-9
[66] Zheng, A. (2005) Molecular genetic and epigenetic mechanisms of hepatocarcinogenesis. Chinese Journal of Cancer, 24, 757-768.
[67] Hussain, S.P., Schwank, J., Staib, F., Wang, X.W. and Harris, C.C. (2007) TP53 mutations and hepatocellular carcinoma: Insights into the etiology and pathogenesis of liver cancer. Oncogene, 26, 2166-2176.
http://dx.doi.org/10.1038/sj.onc.1210279
[68] Kwon, M.J. and Shin, Y.K. (2011) Epigenetic regulation of cancer-associated genes in ovarian cancer. International Journal of Molecular Sciences, 12, 983-1008.
http://dx.doi.org/10.3390/ijms12020983
[69] Wikipedia (2013) Epigenetics. Wikipedia, the free encyclopedia.
http://en.wikipedia.org/wiki/File:Epigenetic_mechanisms.jpg
[70] Wikimedia (2013) The central role of DNA damage and epigenetic defects in DNA repair genes in carcinogenesis.
https://en.m.wikipedia.org/wiki/File:Diagram_Damage_to_Cancer_Wiki_300dpi.svg
[71] Groopman, J.D., Johnson, D. and Kensler, T.W. (2005) Aflatoxin and hepatitis B virus biomarkers: A paradigm for complex environmental exposures and cancer risk. Cancer Biomarkers, 1, 5-14.
[72] Feingold, B.J., Vegosen, L., Davis, M., Leibler, J., Peterson, A. and Silbergeld, E.K. (2010) A niche for infectious disease in environmental health: Rethinking the toxicological paradigm. Environmental Health Perspective, 118, 1165-1172. http://dx.doi.org/10.1289/ehp.0901866
[73] WHO (2002) Aflatoxins (Group 1): Some traditional herbal medicines, some mycotoxins, naphthalene and styrene. World Health Organization International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 82, 171.
http://monographs.iarc.fr/ENG/Monographs/vol82/volume82.pdf
[74] Butler, W.H., Greenblatt, M. and Lijinsky, W. (1969) Carcinogenesis in Rats by aflatoxins B1, G1 and B2. Cancer Research, 29, 2206-2211.
http://cancerres.aacrjournals.org/content/29/12/2206.full.pdf
[75] Eaton, D.L. and Gallagher, E.P. (1994) Mechanisms of aflatoxin carcinogenesis. Annual Review of Pharmacology and Toxicology, 34, 135-172.
http://dx.doi.org/10.1146/annurev.pa.34.040194.001031
[76] Roebuck, B.D., Siegel, W.G. and Wogan, G.N. (1978) In vitro metabolism of aflatoxin B2 by animal and human liver. Cancer Research, 38, 999-1002.
http://cancerres.aacrjournals.org/content/38/4/999.full.pdf
[77] Agag, B.I. (2004) Mycotoxins in foods and feeds 1-aflatoxins. Ass. Univ. Bull. Environ. Res., 7, 173-205.
http://www.aun.edu.eg/env_enc/env%20mar/173-206.PDF
[78] Pascussi, J., Gerbal-Chaloin, S., Duret, C., Daujat-Chavanieu, M., Vilarem, M. and Maurel, P. (2008) The tangle of nuclear receptors that controls xenobiotic metabolism and transport: Crosstalk and consequences. Annual Review of Pharmacology, 48, 1-32.
http://hal.archives-ouvertes.fr/docs/00/16/21/44/PDF/ARPT_Text_23_04.pdf
[79] Xie, W., Barwick, J.L., Simon, C.M., Pierce, A.M., Safe, S., Blumberg, B., Guzelian, P.S. and Evans, R.M. (2000) Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes and Development, 14, 3014-3023.
http://dx.doi.org/10.1101/gad.846800

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