04/07/101 Aflatoxin,Tobacco, and the p53 Tumor Suppressor Gene: Cancer's Missing Link? Kerry Scott...
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Transcript of 04/07/101 Aflatoxin,Tobacco, and the p53 Tumor Suppressor Gene: Cancer's Missing Link? Kerry Scott...
04/07/10 1
Aflatoxin,Tobacco, and the p53 Tumor Suppressor Gene: Cancer's Missing Link?
Kerry Scott Lane M.D. Copyright September 21, 2000
North Carolina State University
04/07/10 2
Aflatoxin And Tobacco What is Aflatoxin Natural Production of Aflatoxin Evidence for Contamination of Tobacco p53 Mutation as Biomarker p53 Tumor Suppressor and All Cancers Aflatoxin and Immunosuppressive States Future Regulatory Framework (FDA-WHO-TART) Future Technology Solutions
04/07/10 3
What is Aflatoxin ?Aflatoxin is a mycotoxin produced by
Aspergillus Flavus, Aspergilli and Penicillium fungi.
It is an complex aromatic heterocycle.It decomposes at 269 C.(Heat stable). AFB
likely survives combustion, especially in ETS.It has profound genetic mutational capabilities
due to its sterospecificity.
04/07/10 4
Natural Production of Aflatoxin Aspergillus is found worldwide, described as a
storage fungus. Aflatoxin production is favored by heat and
humidity. Likely contamination of tobacco is episodic,
random, and even microscopic. Regulated by FDA on corn, grain, peanuts, since
late 1960s. Also regulated by EU countries. Max. permissible level for corn is 20ppb, milk- 0.5
04/07/10 5
Evidence for Contamination of Tobacco Welty and Lucas, NC State 1968 Pattee, NC State 1969 Egypt 1994-El Magrahby India 2000-Guhtka Industry Internal Documents-WARF-1967 Combustion Studies- Kentucky 1970s Combustion Studies-Cincinnati-Lane 1978 Human experiments and p53 biomarkers and
adducts.
04/07/10 6
p53 Mutations as Biomarker p53 is the “Guardian of the genome” which
instructs genetically damaged cells to repair or die. As a tumor suppressor gene it is a last ditch effort
to prevent cancer. p 53 is the most common mutation in all cancers. Most typically laboratory cancer experiments use
aflatoxin to mutate p53. Over 10,000 articles on Medline about aflatoxin
but none had made the aflatoxin-tobacco connection.
04/07/10 7
p53 and most Cancers p53 mutations by aflatoxin at codon 249 AGG to AGT
thought to cause liver cancer. (G-T transversions). Guanines preferentially bound by aflatoxin covalently,
especially poly GG, GGG and GCs. Lung cancer “hotspot” is codon 249, AGG to ATG WHO-IARC database analysis show substantial mutations
in human cancers consistent with aflatoxin etiology. Dennisenko has shown aflatoxin mutates p53 often
consistent with WHO data. Breast cancer shows similar mutational profile. Most cancers show p53 mutations.
04/07/10 8
Lung Cancer Mutational Spectra
0 10 20 30 40 50 60 70
Other
CCC, G-->C, Arg to Pro
CTC, G-->T, Arg to Leu
TGG, C-->T, Arg to Trp
CCG, G-->C, Arg to Pro
Other
AGC, G-->A, Gly to Ser
GTC, G-->T, Gly to Val
Other
AGT, G-->T, Arg to Ser
Other
CAT, G-->A, Arg to His
CCT, G-->C, Arg to Pro
Percentage of substitutions
Codon 249 (AGG)AFB1
Codon 273 (CGT)AFB1, BPDE
Codon 245 (GGC)AFB1
Codon 248 (CGG)AFB1, BPDE
Codon 158 (CGC)Probable AFB1
CpG sites
CpG sites
CpG site
nonCpG site
CpG site
273 n = 67249 n = 59245 n = 56248 n = 51158 n = 41
04/07/10 9
p53, Lung Cancer and ETS
0 5 10 15 20 25 30 35
Other
T-->G
A-->C
nonCpG: G-->A
G-->T
P e rc e n ta g e o f mu ta tio n s
Nonsmoking (n = 136)
Smoking (n = 341)
Nonsmoking (n = 136) 3.68 5.15 8.08 2.94 5.15 0.74 2.94 10.29 6.62 9.56 9.56 4.41 24.26 6.62
Smoking (n = 341) 11.73 1.47 6.16 1.17 1.76 2.05 2.05 9.68 8.21 9.09 4.4 5.57 30.5 6.16
Other nonCpG: T-->C nonCpG: A-->G T-->G T-->A A-->T A-->C CpG: G-->A, C-->T nonCpG: C-->T nonCpG: G-->A C-->G C-->A G-->T G-->C
04/07/10 10
Breast Cancer and AflatoxinPatterns of p53 Substitutions in Breast Cancer
0 5 10 15 20 25
Other
Deletions
nonCpG: T-->C
nonCpG: A-->G
CpG: A-->G
T-->G
T-->A
A-->T
A-->C
CpG: G-->A, C-->T
nonCpG: C-->T
nonCpG: G-->A
C-->G
C-->A
G-->T
G-->C
Percentage of mutations
A:T
bas
e p
airs
G:C
bas
e p
airs
n = 1,448
04/07/10 11
Aflatoxin and Immunosuppression
AFB is a carcinogen, teratogen, mutagen, inhibitor of protein synthesis, and is immunosuppressive.
AFB has been shown to increase HIV levels 500% Smokers have increased HIV levels. Increased HIV levels correlate with increased
infectivity and poorer prognosis. Therefore, AFB contaminated tobacco is likely
contributing to the AIDS pandemic.
04/07/10 12
Future Regulatory Framework (FDA-WHO-TART)
WHO FCTC seeks to regulate toxin levels on tobacco products worldwide by 2003.
TART-Tobacco-Aflatoxin Reduction Talks Aflatoxin and mycotoxin contamination of tobacco
are prime candidates for a Harm Reduction Strategy.
FDA will likely adopt similar guidelines soon. Industry Compliance may provide limited legal
immunity.
04/07/10 13
Future Technology Solutions Multiple solutions available to limit aflatoxin and
mycotoxin production on tobacco products. Monitoring of AFB and mycotoxin contamination from
multiple curing practices will provide valuable data. Prevention, remediation and terminal testing will result in
a less harmful product with less liabilty. Aflatoxin bioinformatics will yield cancer therapies,
vaccines, diagnostic tests, and possibly cures for many human diseases.
04/07/10 14
Aflatoxin and Tobacco
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