Carcinogens- L13 Flashcards Preview

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Flashcards in Carcinogens- L13 Deck (48)
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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
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
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