RED MEAT: eat at your own risk

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RED MEAT eat at your own risk

• Presented by
• Sarah Baird sarah.baird_at_utoronto.ca
• Tara Bromley tara.bromley_at_utoronto.ca
• Christa Connolly christa.connolly_at_utoronto.ca
• Lindsay Coyne lindsay.coyne_at_utoronto.ca

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Outline

• What is red meat?
• How are endogenous toxins formed from red meat?
• The effect of these toxins on the body and their
  link to colorectal cancer
• Pharmacy connection

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What is Red Meat?

• Beef, lamb, venison, and mutton1
• The components of red meat are protein, heme and
  iron2
• Red meat has a higher heme content than white
  meat3

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How do the components of red meat become toxic?

• Heme is easily nitrosylated into a nitrosating
  agent4
• These compounds are capable of donating NO
  groups
• Bacterial enzymes in the intestine break down
  amino acids to form amines and amides2
• The catabolized amino acids are good substrates
  for nitrosation and go on to form N-nitroso
  compounds2
• N-nitroso compounds can be further reduced into
  powerful alkylaters

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DNA Methylation

• As powerful alkylaters, they can methylate DNA
  bases5
• Methylation of DNA bases prevents proper
  base-pairing5
• As a protective mechanism against this
  alkylation, our body produces an enzyme called
  O6-methyl-guanine DNA methyltransferase (MGMT)6

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When MGMT goes wrong

• MGMT removes these methyl groups6
• If the methyl group is not removed, a DNA
  mutation may occur6
• Specifically, if a guanine base is methylated and
  left unrepaired, it will pair with thymine
  instead of cytosine6
• So, during DNA replication, the wild-type G-C
  pair is converted to an A-T pair6

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Lewin, M., Bailey, N., Bandaletova, T., Bowman,
R., Cross, A., Pollock, J., Shuker, D. and
Bingham, S. (2006) Red Meat Enhances the Colonic
Formation of the DNA Adduct O6-Carboxymethyl
Guanine Implications for Colorectal Cancer Risk.
Cancer Research 663 pg. 1859-1864.
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How Does Cancer Occur?

• Cancer occurs when methylation affects tumor
  suppressing genes, silencing their activity and
  preventing housekeeping mechanisms that keep cell
  division in check7
• Hypermethylation of the promoter region of the
  MGMT gene has been shown to silence it's
  expression6
• This is found in approximately 40 of colorectal
  carcinomas6
• Without MGMT, other bases can be methylated and
  there is no longer a mechanism to reverse it

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Colorectal Cancer

• 80 of cases are related to dietary factors3
• Red meat has been linked to colorectal cancer
  because it is the area where bacteria that
  catabolized amino acids into amines and amides
  are present8
• Amines and amides are good substrates for
  nitrosation8
• Once nitrosated, the N-nitroso compounds exhibit
  carcinogenic activity8

Top picture www.mayoclinic.com Bottom two
pictures http//www2.jsasd.k12.pa.us/mhopple/Phys
iology/cancerwebs/Colon20Cancer.htm
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Pharmacy Connection

• Colorectal cancer is the second most common cause
  of cancer related deaths3
• Because there appears to be a dietary component,
  prevention may be possible through lifestyle
  changes
• A balanced diet should be the main focus when
  counseling a patient with concerns about red meat
• Red meat is a good source of nutrients necessary
  for proper growth and nutrition (e.g. B12, iron,
  protein)9

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Summary

• Red Meat contains heme and iron1
• Bacteria in the gut have enzymes that breakdown
  the heme into nitrosating compounds4
• These compounds react with the dietary protein
  from the red meat to make N-nitrosamine compounds
  which are capable of methylating DNA bases2
• Methylation of the bases can cause inactivation
  of tumor supressor genes, such as those for
  MGMT7,6
• Without MGMT, further DNA base methylation cannot
  be reversed, ultimately resulting in DNA
  mutations and potentially uncontrolled cell
  division6
• This uncontrolled cell division in the large
  intestine has been linked to colorectal cancer8

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References

• 1. MayoClinic.com. (2008) MayoClinic.com Tools
  for Healthier Lives, retrieved Feb 10, 2008.
• 2. Bingham, SA, Hughes, R., Cross AJ. (2002)
  Effect of white versus red meat on endogenous
  N-nitrosation in the human colon and further
  evidence of a dose response. Journal of Nutrition
  13211 3522-3535
• 3. Hughes, R., Magee, E., and Bingham, S. (2000)
  Protein Degradation in the Large Intestine
  Relevance to Colorectal Cancer. Current Issues in
  Intestinal Microbiology. 1(2) 51-58.
• 4. Kunhle, GCC., and Bingham, SA. (2007) Dietary
  Meat, Endogenous Nitrosation and Colorectal
  Cancer. Biochemical Society Transactions. 35 pt.
  5 1355-1357
• 5. Lewin, M., Bailey, N., Bandaletova, T.,
  Bowman, R., Cross, A., Pollock, J., Shuker, D.
  and Bingham, S. (2006) Red Meat Enhances the
  Colonic Formation of the DNA Adduct
  O6-Carboxymethyl Guanine Implications for
  Colorectal Cancer Risk. Cancer Research 663 pg.
  1859-1864.
• 6. Esteller, M, Toyota, M, Sanchez-Cespedes, M,
  Capella, G, Peinado, M.A., Watkins, D.N., Issa,
  J.P., Sidransky, D., Baylin, S.B., Herman, J.G.
  (2000). Inactivation of the DNA repair gene
  06-methylguanine-DNA methyltransferase by
  promoter hypermethylation Is associated with G to
  A mutations in K-ras in colorectal tumorigenesis.
  Cancer Research 60 2368-71.
• 7.Linhart, H., Lin, H., Yamada, Y., Moran, E.,
  Steine, E., Gokhale, S., Lo, G., Cantu, E.,
  Ehrich, M., He, T., Meissner, A., and Jaenisc, R.
  (2007) Dnmt3b promotes tumorigensis in vivo by
  gene-specific de novo methylation and
  transcriptional silencing. Genes and Development.
  Accessed Jeb 10, 2008 from http//www.wi.mit.edu/
  news/archives/2007/rj_1201.html
• 8. Cross, A. and Sinha, R. (2004). Meat-Related
  Mutagens/Carcinoge
• ns In the Etiology of Colorectal Cancer.
  Environmental and Molecular Mutagenesis. 4444-55
• 9. Henderson, Jeff (2008). Iron Homeostasis,
  Toxicity and the Treatment of Anemia and
  Hypomethylation, Folic Acid Metabolism and
  Vitamin B12. Given to PHM 226H at the Leslie Dan
  Faculty of Pharmacy, University of Toronto on Jan
  29, 2008 and Jan 30, 2008 respectively.