Carcinogens- L13 Flashcards
What do direct acting carcinogens do ?
react with DNA directly e.g. alkylating agents
What are pro-carcinogens?
compounds metabolically converted to carcinogens after ingestion e.g. aflatoxin, nitrosamines- mostly within food
What is an example of a polyaromatic hydrocarbon ?
benzo[a]pyrene (BP) -it is well known carcinogen in cigarette smoke
What happens to BP when our bodies are exposed to it ?
CYP1A1 metabolises it to the highly reactive mutagenic BP diol epoxide
BP to BP oxide to BP dihydrodiol to BP diol expoxide
each stage is catalysed by p450 enzymes
What alterations for most BP cause?
conversions of G to T
What happens to tobacco when its exposed to our body ?
it is converted to a carcinogen
What are some examples of CYP450 enzymes and their substrates?
1A1= BP, nitrochrysene 1A2= 2-acetylaminofluorene, NNK, aflatoxin B1, protein pyrolysis products 1B= 7,12-dimethylbenzyl[a]anthracene 2E1= benzene, chloroform and vinyl chloride 3A4= aflatoxin B1 and initropyrene
What unfortunate function can p450 enzymes induce?
they are important phase 1 enzymes and they can form ultimate carcinogens form certain ingested chemicals
What is found in the CYP1A1 enzyme in caucasians?
polymorphisms in this enzyme are found in 10%
associated with increased inducibility producing heightened activation of carcinogens in tobacco smoke
What role does N-acetyltransferases (NATs) play?
detoxify aromatic amines in tobacco smoke
What happens in individuals with 2 mutant copies of NATs?
exhibit slow acetylator phenotype, reducing detoxification of aromatic amines and an association with bladder cancer
What do these polymorphisms in CYP450 enzymes mean ?
evidence of these polymorphisms show that differences can alter the outcome
not an all or nothing role but their is evidence demonstrating tendencies
may be that differences in metabolism are responsible for certain carcinogenic effects
What is an example of polymorphism in GST enzymes ?
gene locus for GSTmu is polymorphic man and lacking in 50% caucasians
What does GSTmu do ?
it detoxifies activated epoxides
What do GSTmu null individuals have?
reduced ability to detoxify activated epoxides and high susceptibility to cancer e.g. lung cancer
What is UGT1A1s role ?
involved in estradiol glucuronidation and serum bilirubin conjugation
serum bilirubin is an antioxidant so low UGT might be predictive of cancer risk
What can polymorphisms in UGTs cause?
they have been associated with an increased risk of breast cancer in pre-menopausal african-american women - who have low UGT activity
What do xenobiotic metabolizing enzymes do ?
convert lipophilic compounds to water soluble metabolites excretable in bile or urine i.e. detoxification
or
they can convert lipophilic compounds to electrophiles with potential to react with DNA
What is a problem with the xenobiotic metabolizing enzymes ?
increasing conversion to water soluble metabolites would be beneficial however in an attempt to increase this you may increase the production of electrophiles which would not be beneficial - NOT SIMPLE
also it is necessary to consider the fact that producing the electrophile is sometimes necessary for excretion because phase2 has to metabolise it to help its removal
With pro carcinogen metabolism what is the aim?
- want products of detoxified soluble stable excitable products to occur to a maximum
- want the production of reactive electrophiles that go onto cause mutations to occur to a minimum
BUT part of maximising detoxification may cause increased production of ultimate carcinogens
What are classified as xenobiotics?
low MWt food components
drugs
carcinogens
environmental chemicals
What is the pathway which xenobiotics undergo ?
undergo functionalisation (phase1) to reactive metabolites, or epoxides or carbonium ions or quinines or alkyl halides
then they can either undergo conjugation (phase 2) to water soluble conjugates and be excreted in bile or urine
OR they can undergo binding to DNA which can then either go onto cause cancer or DNA repair occurs
anything to boost DNA repair would be very beneficial
What is the most common mechanism of action for chemical carcinogens?
an electrophile form reacts with nucleophilic sites in the purine and pyrimidine rings of nucleic acids
- some compounds do this directly while others do it after being metabolised and activated in the body to form the ultimate carcinogen
Where are nitrosamines and nitrosamides found?
found in tobacco
found when nitrites used as food preserving agent and react with the amines in meat and fish during smoking
- can react during cooking process or metabolism by gut bacteria which can form compounds that are capable of reacting with nucleic acids
What are heterocyclic amines?
carcinogens formed by cooking meat
derived from proteins and about 20 have been identified
- BBQ meat
- hydrophobic and flat- the flatness enables them get in between DNA base pairs
What will effect the way you handle dietary xenobiotics?
your genetic background - i.e. efficiency of your phase1/phase2 system
What is another thing that your genetic background influences?
it influences your disease risk to a greater or lesser extent
How can you affect the efficiency of your phase1/phase 2 system?
by maximising your genetic potential - inducing good enzymes to max or inhibiting bad enzymes - DIETARY COMPONENTS CAN DO THIS
How can you measure what is going on with ingested carcinogens?
measure markers of activity
e.g. measure aflatoxin exposure you can measure metabolites such as protein lysine adducts
different circumstances enable you to measure different markers
measuring the mutation itself is great but very difficult
What cancer and mutation does aflatoxin cause?
liver cancer
G to C or T to A transversions, particularly codon 248
What cancers and mutations do UV radiation cause?
squamous and basal cell carcinomas
C to T substitutions at dipyrimidine sites
What cancers and mutations does tobacco smoke cause?
lung cancer
G to C or T to A transversions. codons 157, 248, 273
bladder cancer
G to C or T to A transversions
What cancer and mutation does vinyl chloride cause?
angiosarcoma- liver
A-T to T-A transversions
What are biomarkers?
markers of exposure to or damage by a carcinogen- helps to make predictions about exposure
What is an example of aflatoxin biomarker?
aflatoxin B1 DNA adduct
urine and liver cancer
genetic damage increased risk
What is an example of polyaromatic hydrocarbon biomarker?
PAH-DNA adduct
blood, lung and placenta cancer
genetic damage from PAHs in polluted air, cigarrette smoke or at workplaces
What is an example of 4-aminobiphenyl biomarker?
4-aminobiphenyl haemoglobin adducts
blood
active or passive exposure to cigarette smoke
What is an example of thymine glycol biomarker?
thymine glycol
urine
genetic damage form oxidising agents
What are examples of p53 biomarkers?
mutations in the tumour suppressor gene
breast, lung and liver etc
increased risk of various cancers- patterns of mutations may reveal carcinogen which caused damage
What % of cancers have a direct genetic link ?
only 5%
What is a genetic marker of increased risk of lung cancer ?
variations in CYP1A1 gene
found in blood
What is a genetic marker of increased risk for lung and bladder cancer?
absence of GST M1 gene
found in blood
What is a genetic marker of increased risk of breast and other cancers?
H-ras VTR variant of H-ra
found in blood
or
mutations in BRAC1 gene(
What is epidemiology?
it evaluates the distribution and determinants of disease in populations with ultimate goal of prevention
What is molecular epidemiology ?
incorporates molecular genetics, cell biology, biochemistry, statistics and bioethics into traditional epidemiology
What are the 2 major facets of molecular epidemiology ?
1) molecular dosimetry
2) susceptibility studies
What is molecular dosimetry ?
internal dose and biologically effective dose measured with biomarkers
What is susceptibility studies ?
inherited genetic variants evaluated as independent predictors of disease or modifiers of exposure disease relationships
