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Aflatoxin B1

Aflatoxin B1

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Aflatoxin B1

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  1. Aflatoxin B1

  2. Aflatoxin B1: Background • Hepatotoxic mycotoxin (toxin from a fungus) produced by the fungi Aspergillus flavus and Aspergillus parasiticus • Causes aflatoxicosis and liver disease • Aspergillus spp. grow ubiquitously on plants and crops from tropical and subtropical areas: peanuts, figs, spices, corn, maize, Brazil nuts, pecans, walnuts, soybeans, pistachios, wheat and grains

  3. Background • The carcinogenic metabolite of Aflatoxin B1 is found in the milk of mammals who consume contaminated crops • Aspergillus growth and Aflatoxin B1 production is dependant upon the temperature, humidity, host plant type, and the strain of fungus; high humidity usually required for growth • Outbreaks more common in developing countries due to improper drying and storage of crops and a lack of food inspections

  4. Background • Outbreaks occur in groups because of a shared contaminated food supply and the optimal weather conditions for Aspergillus growth • First recorded outbreak was in England in 1960, where 100000 turkeys died.

  5. Background • In 1974 in clustered villages in India, 397 recorded cases with 108 deaths; this was preceded by an outbreak in the local dogs • In Kenya in 2004, maize contaminated with Aflatoxin B1 caused liver disease and jaundice in 317 people; 125 people died The use of antifungal agents is often too costly for farmers in developing countries

  6. ToxicityParameters • Exposure to 2-6 mg of aflatoxin by consumption daily for one month is cited to have toxic effects (David et al. 1994) • Consumption of 55 µg/ kg of aflatoxin daily for an unknown period of time will be fatal (FDA 1992) • However, levels found to be toxic are inconsistent between various studies. • Reasons for this include: • 1) most studies were done in African countries where prevalence of Heptatitis B is very high • 2) Active HepB virus is known to be synergistic with aflatoxin in causing toxicities and hepatocellular carcinoma

  7. Toxicitycont’d 3) most studies were done on rats, and it can be difficult to extrapolate these results to humans 4) There is a double standard for accepted aflatoxin levels due to economic stress: • food intended for human consumption must have less than 30ppb, and animal feed may be as high as 30ppb in America

  8. Mechanism of Action • AFB1 is oxidized by CYT P450 in the liver into AFB1-8,9-epoxide which is the major metabolite that exerts hepatotoxic effects • The 8,9 epoxide is neutralized by conjugation in the liver with GSH (glutathione) by glutathione-S-transferase, an enzyme abundant in some animals (mice), but which rats and humans are relatively deficient in.

  9. Mechanism of Action • The 8,9 epoxide binds preferentially to mitochondrial DNA hindering ATP production and FAD/NAD-linked enzymatic functions. The result is reduced mitochondrial function and increased prevalence of mitochondrial directed apoptosis • GSH has many roles in membrane maintenance and stability as well as reducing oxidative stress. Its reduction further enhances the damage to critical cellular components (DNA, lipids, proteins) by the 8,9 epoxides

  10. Mechanism of Action • Abnormally high levels of ROS are found in cells affected by aflatoxin due to uncoupling of metabolic processes resulting from the lack of GSH for GSH-peroxidase catalysis of O2· to H2O2 leading to lipid peroxidation and compromised cell membranes

  11. AFB1-8,9-epoxide Is Cancer-causing!! • One of the most serious effects of the AFB1-8,9-epoxide metabolite is it reacts with amino acids in DNA and forms an adduct. • This adduct is fairly resistant to DNA repair processes and thus this gene mutation may cause carcinoma of the liver. • CYP 3A4 is the major CYP 450 enzyme responsible for activation of AFB1 into the epoxide form. • However, the liver can detoxify AFB1 by oxidizing it to other metabolites such as AFQ1 which has very little cancer-causing potential. These are usually excreted in urine with little effect on the body. (Novoa and Diaz 2006)

  12. When the epoxide combines with DNA or RNA, it forms what is known as an adduct

  13. How Does Aflatoxin Cause Cancer? • Inactivation of the p53 tumor suppressor gene enables mutation of Codon 249 (primary gene mutation caused specifically by AFB1) • This shuts off the gene and potentially allows for uncontrolled cell proliferation. • But exposure to aflatoxin does not necessarily predispose you to liver cancer. • The human body is capable of genetic repairs and some people are more resistant to cancer than others

  14. Other Adverse Effects of AFB1-8,9-epoxide • Lipid accumulation in the liver due to decreased lipid transport and reduced oxidation • Symptoms of liver failure occur with acute aflatoxicosis: • Jaundice • ascites (fluid build up) • portal hypertension • necrosis of the liver

  15. Other Adverse Effects of AFB1-8,9-epoxide • The binding of the epoxide with proteins may: • Inhibit the protein from performing its enzymatic functions • Create a reservoir of the toxin in proteins, prolonging exposure

  16. Metabolism • Both metabolized and unmetabolized aflatoxin is excreted mostly in urine. It is also excreted in milk, stool, feces, and saliva (which may be swallowed and re-enter the GI tract)

  17. Other Chronic Effects of Aflatoxin • Immunological Suppression • Using animal models, AFB1 has been shown to impair normal immune function either by reducing phagocytic activity or reduce T cell number and function. • Nutritional Interference • Aflatoxin is shown to have a dose response relationship between exposure to aflatoxin and rate of growth among small children. In addition, it also interferes in nutrient modification such as VitaminA or D in animal models.

  18. The Good News… • In general, the incidence of toxicity and cancer is quite low after toxin exposure • The liver is very efficient in removing it from the body in most cases • However, children are more susceptible to toxicity because their metabolic enzyme systems are not fully developed

  19. Treatment • Inactivation of toxin in plants before mammalian ingestion: • Synergistic combination of gamma radiation and hydrogen peroxide degrades the toxin • Treatment of corn with ammonia • Dichlorvos (an insecticide) inhibits aflatoxin B1 biosynthesis • NaHSO3 soak for corn also shows beneficial results in removing the toxin

  20. Treatment • After ingestion • Treatment with antibiotics or other drugs has little effect • Chlorophyll intervention: supplement diets with foods rich in chlorophyll (such as wheatgrass and alfalfa) • Blocks carcinogen bioavailability • Certain types of flavanoids found in grapefruit stimulates the microsomal activation of aflatoxin B1 to the exo-8,9-epoxide which is not harmful • Administration of drugs that induce hepatic detoxification enzymes (ethoxyquin, butylated hydroxyanisol, butylated hydroxytuluene, phenobarbital) • Oltipraz (a chemopreventative agent curretntly undergoing phase I trials in the United States) inhibits aflatoxin B1 mediated hepatocarcinogens in rats • The possibility of induction of an antibody that would allow the body to identify and remove the toxin upon exposure (aflatoxin B1- lysine adduct monoclonal antibody) is currently being researched

  21. THE END

  22. Literature Cited • Urrego Novoa JR and Diaz GJ. 2006. Aflatoxins and its mechanisms of toxicity in hepatic cancer. Rev.fac.med.unal. 54: 108-116. Available from World Wide Web: <http://www.scielo.org.co/scielo.php?script=sci_arttext&pid=S0120-00112006000200006&lng=en&nrm=iso>. • Eaton DL and Gallagher EP. 1994. Mechanism of aflatoxin carcinogenesis. Annual review of pharmacology and toxicology 34: 135-172. • U.S. Food And Drug Administration. “Bad Bug Book: Alfatoxins”. June 14, 2006. <http://www.cfsan.fda.gov/~mow/chap41.html> • Center For Disease Control. Morbidity and Mortality Weekly Report. “Outbreak of Aflatoxin Poisoning - Eastern and Central Provinces, Kenya, January-July 2004”. Sept. 3, 2004. <http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5334a4.htm> • Reddy, S.V., Waliyar, Farid. “Properties of aflatoxin and it producing fungi”. Oct. 11, 2007. http://www.icrisat.org/aflatoxin/aflatoxin.asp • R. J. Verma. 2004. Aflatoxin Cause DNA Damage. International Journal of Human Genetics 4(4): 231-236. • J. H. Williams, et al. 2004. Human aflatoxicosis in developing countries: a review of toxicology, exposure, potential health consequences, and interventions. The American Journal of Clinical Nutrition. 80:1106 –22 • Patricia A. Egner, et al. Chlorophyllin intervention reduces aflatoxin–DNA adducts in individuals at high risk for liver cancer. Proc Natl Acad Sci U S A. 2001 December 4; 98(25): 14601–14606. Published online 2001 November 27. • L I McLellan, et. al; Regulation of aflatoxin B1-metabolizing aldehyde reductase and glutathione S-transferase by chemoprotectors. Biochem J. 1994 May 15; 300(Pt 1): 117–124. • F P Guengerich, et. al.; Interactions of ingested food, beverage, and tobacco components involving human cytochrome P4501A2, 2A6, 2E1, and 3A4 enzymes. Environ Health Perspect. 1994 November; 102(Suppl 9): 49–53. • Jia-Sheng Wang, et al; Development of Aflatoxin B1-Lysine Adduct Monoclonal Antibody for Human Exposure Studies. Appl Environ Microbiol. 2001 June; 67(6): 2712–2717. doi: 10.1128/AEM.67.6.2712-2717.2001.

  23. Literature Cited • Google Images: http://www.takingdownwords.com/photos/uncategorized/turkey.jpg • Google Images: http://www.sfws.auburn.edu/sfnmc/class/fy614/fungicide.jpg • Google Images: http://www.cals.cornell.edu/cals/public/impact/images/cows-eating-dairy-impact.jpg • Google Images: http://www.revmed.unal.edu.co/revistafm/v54n2/imagenes/v54n2a06fig5.jpg • Google Images: http://www.merck.com/media/mmhe2/thumbnails/tn_10116ap.jpg • Google Images: http://sitemaker.umich.edu/section4group6/files/12_row_machine_in_corn.jpg • Google Images: http://www.agry.purdue.edu/ext/forages/images/alfalfa_leaf.JPG • M. Smela et. al; The chemistry and biology of aflatoxin B1: from muational spectrometry to carcinogenesis. Carcinogenesis, vol.22, p 535-45, 1994 • M. McLean, M. Dutton; Cellular interactions and metabolism of aflatoxin: an update. Pharmacological Therapeutics, vol.65, p163-92, 1995 • Google Images: http://www.biocom.arizona.edu/graphics/images/projects/liver.jpg • Google Images: http://129.215.156.68/Images/Asexual%20structures%20of%20Aspergillus%20niger.jpg • Kensler, T W; Chemoprevention by inducers of carcinogen detoxication enzymes. Environ Health Perspect. 1997 June; 105(Suppl 4): 965–970. • U D Patel, P Govindarajan, and P J Dave; Inactivation of aflatoxin B1 by using the synergistic effect of hydrogen peroxide and gamma radiation. Appl Environ Microbiol. 1989 February; 55(2): 465–467. • O L Brekke, et. Al; Aflatoxin in corn: ammonia inactivation and bioassay with rainbow trout. Appl Environ Microbiol. 1977 July; 34(1): 34–37. • Raymond C. Yao and Dennis P. H. Hsieh; Step of Dichlorvos Inhibition in the Pathway of Aflatoxin Biosynthesis. Appl Microbiol. 1974 July; 28(1): 52–57.