Advertisement

Archives of Toxicology

, Volume 88, Issue 9, pp 1635–1644 | Cite as

Metabolism of aflatoxins: key enzymes and interindividual as well as interspecies differences

  • Vlastimil Dohnal
  • Qinghua Wu
  • Kamil Kuča
Review Article

Abstract

Aflatoxins are potent hepatocarcinogen in animal models and suspected carcinogen in humans. The most important aflatoxin in terms of toxic potency and occurrence is aflatoxin B1 (AFB1). In this review, we mainly summarized the key metabolizing enzymes of AFB1 in animals and humans. Moreover, the interindividual and the interspecies differences in AFB1 metabolism are highly concerned. In human liver, CYP3A4 plays an important role in biotransforming AFB1 to the toxic product AFB1-8,9-epoxide. In human lung, CYP2A13 has a significant activity in metabolizing AFB1 to AFB1-8,9-epoxide and AFM1-8,9-epoxide. The epoxide of AFB1-8,9-epoxide could conjugate with glutathione to reduce the toxicity by glutathione-S-transferase (GST). In poultry species, CYP2A6, CYP3A37, CYP1A5, and CYP1A1 are responsible for bioactivation of AFB1. There are interindividual variations in the rate of activation of aflatoxins in various species, and there are also differences between children and adults. The age and living regions are important factors affecting resistance of species to AFB1. The rate of AFB1-8,9-epoxide formation and its conjugation with glutathione are key parameters in interspecies and interindividual differences in sensitivity to the toxic effect of AFB1. This review provides an important information for key metabolizing enzymes and the global metabolism of aflatoxins in different species.

Keywords

Aflatoxins AFB1 Metabolizing enzymes Metabolism Interindividual Interspecies differences 

Abbreviations

IARC

International Agency for Research in Cancer

HCC

Hepatocellular carcinoma

AFBO

AFB1-8,9-epoxide

AFB1

Aflatoxin B1

AFL

Aflatoxicol

CYP450

Cytochrome P450

GSH

Glutathione

GST

Glutathione-S-transferase

mEH

Microsomal epoxide hydrolase

AFAR

Aflatoxin-aldehyde reductase

LOX

Lipoxygenase

PHS

Rostaglandin H

Notes

Acknowledgments

This work was financially supported by the Project of Excellence FIM UHK and by MH CZ – DRO (UHHK, 00179906).

Conflict of interest

The authors report no conflicts of interest.

References

  1. Ball RW, Coulombe RA Jr (1991) Comparative biotransformation of aflatoxin B1 in mammalian airway epithelium. Carcinogenesis 12:305–310PubMedCrossRefGoogle Scholar
  2. Bedard LL, Massey TE (2006) Aflatoxin B1-induced damage and its repair. Cancer Lett 241:174–183PubMedCrossRefGoogle Scholar
  3. Borroz KI, Ramsdell HS, Eaton DL (1991) Mouse strain differences in glutathione S-transferase activity and aflatoxin B1 biotransformation. Toxicol Lett 58(1):97–105PubMedCrossRefGoogle Scholar
  4. Breinholt V, Schimerlik M, Dashwood R, Bailey G (1995) Mechanisms of chlorophyllin anticarcinogenesis against aflatoxin B1. Complex formation with the karcinogen. Chem Res Toxicol 8:506–514PubMedCrossRefGoogle Scholar
  5. Chou MW, Chen W (1997) Food restriction reduces aflatoxin B1 (AFB1)-DNA adduct formation, AFB1-glutathione conjugation, and DNA damage in AFB1-treated male F344 rats and B6C3F1 mice. J Nutr 27(2):210–217Google Scholar
  6. Diaz GJ, Murcia HW, Cepeda SM (2010a) Cytochrome P450 enzymes involved in the metabolism of aflatoxin B1 in chickens and quail. Poult Sci 89:2461–2469PubMedCrossRefGoogle Scholar
  7. Diaz GJ, Murcia HW, Cepeda SM (2010b) Bioactivation of aflatoxin B1 by turkey liver microsomes: responsible cytochrome P450 enzymes. Brit Poult Sci 51:828–837CrossRefGoogle Scholar
  8. Donnelly PJ, Stewart RK, Ali SL, Conlan AA, Reid KR, Petsikas D, Massey TE (1996) Biotransformation of aflatoxin B1 in human lung. Carcinogenesis 17(11):2487–2494PubMedCrossRefGoogle Scholar
  9. Dutton MF (1988) Enzymes and aflatoxin biosynthesis. Microbiol Rev 52:274–295PubMedCentralPubMedGoogle Scholar
  10. Eaton DL, Bammler TK, Kelly EJ (2001) Interindividual differences in response to chemoprotection against aflatoxin-induced hepatocarcinogenesis: implications for human biotransformation enzyme polymorphisms. Adv Exp Med Biol 500:559–576PubMedCrossRefGoogle Scholar
  11. Emafo PO (1976) Species differences in the metabolism of aflatoxin B1. Afr J Med Med Sci 5:55–62PubMedGoogle Scholar
  12. Forrester LM, Neal GE, Judah DJ, Glancey MJ, Wolf CR (1990) Evidence for involvement of multiple forms of cytochrome P-450 in aflatoxin B1 metabolism in human liver. Proc Natl Acad Sci USA 87(21):8306–8310PubMedCentralPubMedCrossRefGoogle Scholar
  13. Fukuhara M, Antignac E, Fukusen N, Kato K, Kimura M (1994) Characterization of cytochrome P450-monooxygenases of Chinese hamsters with respect to aflatoxin B1 activation. Toxicology 93:165–173PubMedCrossRefGoogle Scholar
  14. Groopman JD, Donahue PR, Zhu JQ, Chen JS, Wogan GN (1985) Aflatoxin metabolism in humans: detection of metabolites and nucleic acid adducts in urine by affinity chromatography. Proc Natl Acad Sci USA 82(19):6492–6496PubMedCentralPubMedCrossRefGoogle Scholar
  15. Groopman JD, Zhu JQ, Donahue PR, Pikul A, Zhang LS, Chen JS, Wogan GN (1992a) Molecular dosimetry of urinary aflatoxin-DNA adducts in people living in Guangxi Autonomous Region, People’s Republic of China. Cancer Res 52(1):45–52PubMedGoogle Scholar
  16. Groopman JD, Hall AJ, Whittle H, Hudson GJ, Wogan GN, Montesano R, Wild CP (1992b) Molecular dosimetry of aflatoxin-N7-guanine in human urine obtained in The Gambia, West Africa. Cancer Epidemiol Biomark Prev 1(3):221–227Google Scholar
  17. Groopman JD, Roebuck BD, Kensler TW (1992c) Molecular dosimetry of aflatoxin DNA adducts in humans and experimental rat models. Prog Clin Biol Res 374:139–155PubMedGoogle Scholar
  18. Gross-Steinmeyer K, Eaton DL (2012) Dietary modulation of the biotransformation and genotoxicity of aflatoxin B1. Toxicology 299:69–79PubMedCrossRefGoogle Scholar
  19. Guengerich FP, Johnson WW, Shimada T, Ueng YF, Yamazaki H, Langouët S (1998) Activation and detoxication of aflatoxin B1. Mutat Res 402(1–2):121–128PubMedCrossRefGoogle Scholar
  20. Gurtoo HL, Motycka L (1976) Effect of sex difference on the in vitro and in vivo metabolism of aflatoxin B1 by the rat. Cancer Res 36(12):4663–4671PubMedGoogle Scholar
  21. Halvorson MR, Phillips TD, Safe SH, Robertson LW (1985) Metabolism of aflatoxin B1 by rat hepatic microsomes induced by polyhalogenated biphenyl congeners. Appl Environ Microb 49:882–886Google Scholar
  22. Hayes JD, Judah DJ, McLellan LI, Neal GE (1991) Contribution of the glutathione S-transferases to the mechanisms of resistance to aflatoxin B1. Pharmacol Ther 50:443–472PubMedCrossRefGoogle Scholar
  23. He XY, Tang L, Wang SL, Cai QS, Wang JS, Hong JY (2006) Efficient activation of aflatoxin B1 by cytochrome P450 2A13, an enzyme predominantly expressed in human respiratory tract. Int J Cancer 118(11):2665–2671PubMedCrossRefGoogle Scholar
  24. Helferich WG, Baldwin RL, Hsieh DP (1986) [14C]-aflatoxin B1 metabolism in lactating goats and rats. J Anim Sci 62(3):697–705PubMedGoogle Scholar
  25. IARC (2012) A review of human carcinogens: chemical agents and related occupations. 100: 225–244Google Scholar
  26. Jouany JP (2007) Methods for preventing, decontaminating and minimizing the toxicity of mycotoxins in feeds. Anim Feed Sci Technol 137:342–362CrossRefGoogle Scholar
  27. Kamdem LK, Meineke I, Gödtel-Armbrust U, Brockmöller J, Wojnowski L (2006) Dominant contribution of P450 3A4 to the hepatic carcinogenic activation of aflatoxin B1. Chem Res Toxicol 19(4):577–586PubMedCrossRefGoogle Scholar
  28. Karenlampi SO (1984) Mechanism of cytotoxicity of aflatoxin B1: role of cytochrome P1-450. Biochem Biophys Res Commun 145:854–860CrossRefGoogle Scholar
  29. Kelly JD, Eaton DL, Guengerich FP, Coulombe RA Jr (1997) Aflatoxin B1 activation in human lung. Toxicol Appl Pharmacol 144(1):88–95PubMedCrossRefGoogle Scholar
  30. Kirby GM, Wolf CR, Neal GE, Judah DJ, Henderson CJ, Srivatanakul P, Wild CP (1993) In vitro metabolism of aflatoxin B1 by normal and tumorous liver tissue from Thailand. Carcinogenesis 14(12):2613–2620PubMedCrossRefGoogle Scholar
  31. Kirby GM, Batist G, Alpert L, Lamoureux E, Cameron RG, Alaoui-Jamali MA (1996) Overexpression of cytochrome P-450 isoforms involved in aflatoxin B1 bioactivation in human liver with cirrhosis and hepatitis. Toxicol Pathol 24:458–467PubMedCrossRefGoogle Scholar
  32. Kitada M, Taneda M, Ohta K, Nagashima K, Itahashi K (1990) Kamataki T (1990) Metabolic activation of aflatoxin B1 and 2-amino-3-methylimidazo[4,5-f]-quinoline by human adult and fetal livers. Cancer Res 50(9):2641–2645PubMedGoogle Scholar
  33. Klein Patrick J, Buckner Robert, Kelly Jack, Coulombe Roger A Jr (2000) Biochemical basis for the extreme sensitivity of Turkeys to aflatoxin B1. Toxicol Appl Pharmacol 165:45–52PubMedCrossRefGoogle Scholar
  34. Klein PJ, Van Vleet TR, Hall JO, Coulombe RA Jr (2002) Biochemical factors underlying the age-related sensitivity of turkeys to aflatoxin B1. Comp Biochem Phys C 132:193–201CrossRefGoogle Scholar
  35. Kuilman MEM, Maas RFM, Fink-Gremmels J (2000) Cytochrome P450-mediated metabolism and cytotoxicity of aflatoxin B1 in bovine hepatocytes. Toxicology 14:321–327Google Scholar
  36. Larsson P, Tjälve H (1995) Extrahepatic bioactivation of aflatoxin B1 in fetal, infant and adult rats. Chem Biol Interact 94(1):1–19PubMedCrossRefGoogle Scholar
  37. Larsson P, Tjälve H (1996) Bioactivation of aflatoxin B1 in the nasal and tracheal mucosa in swine. J Anim Sci 74:1672–1680PubMedGoogle Scholar
  38. Larsson P, Pettersson H, Tjalve H (1989) Metabolism of aflatoxin B1 in the bovine olfactory mucosa. Carcinogenesis 10:1113–1118PubMedCrossRefGoogle Scholar
  39. Larsson P, Persson E, Tyden E, Tjälve H (2003) Cell-specific activation of aflatoxin B1 correlates with presence of some cytochrome P450 enzymes in olfactory and respiratory tissues in horse. Reas Vet Sci 74:227–233CrossRefGoogle Scholar
  40. Loveland PM, Wilcox JS, Pawlowski NE, Bailey GS (1987) Metabolism and DNA binding of aflatoxicol and aflatoxin B1 in vivo and in isolated hepatocytes from rainbow trout (Salmo gairdneri). Carcinogenesis 8(8):1065–1070PubMedCrossRefGoogle Scholar
  41. Lozano MC, Diaz GJ (2006) Microsomal and cytosolic biotransformation of aflatoxin B1 in four poultry species. Brit Poult Sci 47:734–741CrossRefGoogle Scholar
  42. Maheo K, Morel F, Langouet S, Kramer H, Le Ferrec E, Ketterer B, Guillouzo A (1997) Inhibition of cytochromes P-450 and induction of glutathione S-transferases by sulforaphane in primary human and rat hepatocytes. Cancer Res 57:3649–3652PubMedGoogle Scholar
  43. Massey TE, Smith GB, Tam AS (2000) Mechanisms of aflatoxin B1 lung tumorigenesis. Exp Lung Res 26(8):673–683PubMedCrossRefGoogle Scholar
  44. Mclean M, Dutton MF (1995) Cellular interactions and metabolism of aflatoxin: an update. Pharmacol Ther 65:163–192PubMedCrossRefGoogle Scholar
  45. Metcalfe SA, Neal GE (1983) The metabolism of aflatoxin B1 by hepatocytes isolated from rats following the in vivo administration of some xenobiotics. Carcinogenesis 4:1007–1012PubMedCrossRefGoogle Scholar
  46. Mykkänen H, Zhu H, Salminen E, Juvonen RO, Ling W, Ma J, Polychronaki N, Kemiläinen H, Mykkänen O, Salminen S, El-Nezami H (2005) Fecal and urinary excretion of aflatoxin B1 metabolites (AFQ1, AFM1 and AFB-N7-guanine) in young Chinese males. Int J Cancer 115(6):879–884PubMedCrossRefGoogle Scholar
  47. Neal GE, Judah DJ, Green JA (1986) The in vitro metabolism of aflatoxin B1 catalyzed by hepatic microsomes isolated from control or 3-methylcholanthrene-stimulated rats and quail. Toxicol Appl Pharmacol 82(3):454–460PubMedCrossRefGoogle Scholar
  48. Neal GE, Nielsch U, Judah DJ, Hulbert PB (1987) Conjugation of model substrates or microsomally-activated aflatoxin B1 with reduced glutathione, catalysed by cytosolic glutathione-S-transferases in liver of rats, mice and guinea pig. Biochem Pharmacol 36:4269–4276PubMedCrossRefGoogle Scholar
  49. Neal GE, Eaton DL, Judah DJ, Verma A (1998) Metabolism and toxicity of aflatoxins M1 and B1 in human-derived in vitro systems. Toxicol Appl Pharmacol 151(1):152–158PubMedCrossRefGoogle Scholar
  50. Niu G, Wen Z, Rupasinghe SG, Zeng RS, Berenbaum MR, Schuler MA (2008) Aflatoxin B1 detoxification by CYP321A1 in Helicoverpa zea. Arch Insect Biochem Physiol 69(1):32–45PubMedCrossRefGoogle Scholar
  51. Partanen HA, El-Nezami HS, Leppänen JM, Myllynen PK, Woodhouse HJ, Vähäkangas KH (2010) Aflatoxin B1 transfer and metabolism in human placenta. Toxicol Sci 113(1):216–225PubMedCrossRefGoogle Scholar
  52. Pelkonen P, Kirby GM, Wild CP, Bartsch H, Lang MA (1994) Metabolism of nitrosamine and aflatoxin B1 by haster liver CYP2A enzymes. Chem Biol Interact 93:41–50PubMedCrossRefGoogle Scholar
  53. Pelkonen P, Lang MA, Negishi M, Wild CP, Juvonen RO (1997) Interaction of aflatoxin B1 with cytochrome P450 2A5 and its mutants: correlation with metabolic activation and toxicity. Chem Res Toxicol 10(1):85–90PubMedCrossRefGoogle Scholar
  54. Polychronaki N, Wild CP, Mykkänen H, Amra H, Abdel-Wahhab M, Sylla A, Diallo M, El-Nezami H, Turner PC (2008) Urinary biomarkers of aflatoxin exposure in young children from Egypt and Guinea. Food Chem Toxicol 46:519–526PubMedCrossRefGoogle Scholar
  55. Putt DA, Ding X, Coon MJ, Hollenberg PF (1995) Metabolism of aflatoxin B1 by rabbit and rat nasal mucosa microsomes and purified cytochrome P450, including isoforms 2A10 and 2A11. Carcinogenesis 16:1411–1417PubMedCrossRefGoogle Scholar
  56. Ramsdell HS, Eaton DL (1990) Species susceptibility to aflatoxin B1 carcinogenesis: comparative kinetics of microsomal biotransformation. Cancer Res 50:615–620PubMedGoogle Scholar
  57. Rawal S, Coulombe RA Jr (2011) Metabolism of aflatoxin B1 in turkey liver microsomes: the relative roles of cytochromes P450 1A5 and 3A37. Toxicol Appl Pharmacol 254(3):349–354PubMedCrossRefGoogle Scholar
  58. Rawal S, Kim JE, Coulombe RA Jr (2010a) Aflatoxin B1 in poultry: toxicology, metabolism and prevention. Res Vet Sci 89:325–331PubMedCrossRefGoogle Scholar
  59. Rawal S, Yip SS, Coulombe RA Jr (2010b) Cloning, expression and functional characterization of cytochrome P450 3A37 from turkey liver with high aflatoxin B1 epoxidation activity. Chem Res Toxicol 23(8):1322–1329PubMedCrossRefGoogle Scholar
  60. Roebuck BD, Wogan GN (1977) Species comparison of in vitro metabolism of aflatoxin B1. Cancer Res 37:1649–1656PubMedGoogle Scholar
  61. Roy SK, Kulkarni AP (1997) Aflatoxin B1 epoxidation catalysed by partially purified human liver lipoxygenase. Xenobiotica 27:231–241PubMedCrossRefGoogle Scholar
  62. Salhab AS, Edwards GS (1977) Comparative in vitro metabolism of aflatoxicol by liver preparations from animals and humans. Cancer Res 37:1016–1021PubMedGoogle Scholar
  63. Sawada M, Kitamura R, Norose T, Kitada M, Itahashi K, Kamataki T (1993) Metabolic activation of aflatoxin B1 by human placental microsomes. J Toxicol Sci 18(2):129–132PubMedCrossRefGoogle Scholar
  64. Shimada T, Guengerich FP (1989) Evidence for cytochrome P-45ONF, the nifedipine oxidase, being the principal enzyme involved in the bioactivation of aflatoxins in human liver. Proc Natl Acad Sci USA 86:462–465PubMedCentralPubMedCrossRefGoogle Scholar
  65. Thompson EE, Kuttab-Boulos H, Yang L, Roe BA, Rienzo AD (2006) Sequence diversity and haplotype structure at the human CYP3A cluster. Pharmacogenomics J 6:105–114PubMedCrossRefGoogle Scholar
  66. Toledo C, Hendricks J, Loveland P, Wilcox J, Bailey G (1987) Metabolism and DNA-binding in vivo of aflatoxin B1 in medaka (Oryzias latipes). Comp Biochem Physiol C 7(2):275–281CrossRefGoogle Scholar
  67. Troxel CM, Reddy AP, O’Neal PE, Hendricks JD, Bailey GS (1997) In vivo aflatoxin B1 metabolism and hepatic DNA adduction in zebrafish (Danio rerio). Toxicol Appl Pharmacol 143:213–220PubMedCrossRefGoogle Scholar
  68. Tulayakul P, Sakuda S, Dong KS, Kumagai S (2005) Comparative activities of glutathione-S-transferase and dialdehyde reductase toward aflatoxin B1 in livers of experimental and farm animals. Toxicon 46:204–209PubMedCrossRefGoogle Scholar
  69. Tulayakul P, Dong K, Kumagai S (2006) Organ differences in microsomes and cytosol metabolism of Aflatoxin B1 in piglets. Toxicol Environ Chem 88:479–487CrossRefGoogle Scholar
  70. Ueng YF, Shimada T, Yamazaki H, Guengerich FP (1995) Oxidation of aflatoxin B1 by bacterial recombinant human cytochrome P450 enzymes. Chem Res Toxicol 8(2):218–225PubMedCrossRefGoogle Scholar
  71. Van Vleet TR, Klein PJ, Coulombe RA Jr (2001) Metabolism of aflatoxin B1 by normal human bronchial epithelial cells. J Toxicol Env Heal A 63:525–540CrossRefGoogle Scholar
  72. Van Vleet TR, Klein PJ, Coulombe RA (2002) Metabolism and cytotoxicity of aflatoxin B-1 in cytochrome P-450-expressing human lung cells. J Toxicol Env Heal A 65:853–867CrossRefGoogle Scholar
  73. Wang C, Bammler TK, Guo Y, Kelly EJ, Eaton DL (2000) Mu-class GSTs are responsible for aflatoxin B(1)-8, 9-epoxide-conjugating activity in the nonhuman primate macaca fascicularis liver. Toxicol Sci 56:26–36PubMedCrossRefGoogle Scholar
  74. Wild CP, Jiang YZ, Allen SJ, Jansen LA, Hall AJ, Montesano R (1990) A flatoxin-albumin adducts in human sera from different regions of the world. Carcinogenesis 11:2271–2274PubMedCrossRefGoogle Scholar
  75. Wolff T, Distlerath LM, Worthington MT, Groopman JD, Hammons GJ, Kadlubar FF, Prough RA, Martin MV, Guengerich FP (1985) Substrate specificity of human liver cytochrome P-450 debrisoquine 4-hydroxylase probed using immunochemical inhibition and chemical modeling. Cancer Res 45:2116–2122PubMedGoogle Scholar
  76. Wu Q, Jezkova A, Yuan Z, Pavlikova L, Dohnal V (2009) Biological degradation of aflatoxins. Drug Metab Rev 41(1):1–7PubMedCrossRefGoogle Scholar
  77. Yanagimoto T, Itoh S, Sawada M, Hashimoto H, Kamataki T (1994) Molecular cloning and functional expression of a mouse cytochrome p-450 (P4503a-13): examination of P450 3a-13 enzyme to activate aflatoxin B1 (AFB1). Biochim Biophys Acta 1201:405–410PubMedCrossRefGoogle Scholar
  78. Yang XJ, Lu HY, Li ZY, Bian Q, Qiu LL, Li Z, Liu Q, Li J, Wang X, Wang SL (2012) Cytochrome P450 2A13 mediates aflatoxin B1-induced cytotoxicity and apoptosis in human bronchial epithelial cells. Toxicology 300(3):138–148PubMedCrossRefGoogle Scholar
  79. Yang X, Zhang Z, Wang X, Wang Y, Zhang X, Lu H, Wang SL (2013) Cytochrome P450 2A13 enhances the sensitivity of human bronchial epithelial cells to aflatoxin B1-induced DNA damage. Toxicol Appl Pharmacol 270(2):114–121PubMedCrossRefGoogle Scholar
  80. Yourtee DM, Rohrig TP (1985) The in vitro metabolism of aflatoxin Q1 by mouse and rabbit liver preparations. Res Commun Chem Pathol Pharmacol 50:103–123PubMedGoogle Scholar
  81. Zeng RS, Niu G, Wen Z, Schuler MA, Bernbaum MR (2006) Toxicity of aflatoxin B1 to Helicoverpa zea and bioactivation by cytochrome P450 monooxygenases. J Chem Ecol 32:1459–1471PubMedCrossRefGoogle Scholar
  82. Zhang Z, Yang X, Wang Y, Wang X, Lu H, Zhang X, Xiao X, Li S, Wang X, Wang SL (2013) Cytochrome P450 2A13 is an efficient enzyme in metabolic activation of aflatoxin G1 in human bronchial epithelial cells. Arch Toxicol 87(9):1697–1707PubMedCrossRefGoogle Scholar
  83. Zhang Z, Lu H, Huan F, Meghan C, Yang X, Wang Y, Wang X, Wang X, Wang SL (2014) Cytochrome P450 2A13 mediates the neoplastic transformation of human bronchial epithelial cells at a low concentration of aflatoxin B1. Int J Cancer 134(7):1539–1548PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Chemistry, Faculty of ScienceUniversity of Hradec KraloveHradec KraloveCzech Republic
  2. 2.College of Life ScienceYangtze UniversityJingzhouChina
  3. 3.Faculty of Informatics and Management Center for Basic and Applied ResearchUniversity of Hradec KraloveHradec KraloveCzech Republic
  4. 4.Biomedical Research CenterUniversity Hospital Hradec KraloveHradec KraloveCzech Republic

Personalised recommendations