Chemical carcinogens 1 Flashcards
how many diagnoses of cancer are there each year ?
about 14 million
what are the 5 main groups of chemical carcinogens ?
alkylating agents - react directly with DNA to form covalent bonds
aromatic amines- used to be used in synthetic dyes
azo dyes- no longer used as food colourants and cosmetic products
nitroso compounds
polycyclic aromatic hydrocarbons (PAHs)- best studied and come into contact with them every day
how many people each year die from cancer ?
6-7 million
how much of cancers have an environmental cause and what are they ?
80% exposure to radiation- UV and ionising exposure to toxins exposure to oncogenic viruses exposure to man made carcinogenic materials
what are polycyclic aromatic hydrocarbons ?
largest group of chemical carcinogens
several hundred chemically related compounds
consist largely of hydrogens are carbons
why are PAHs ubiquitous ?
they are readily formed when organic material is combusted - forest fires, anthropogenic activity such as automobile engines, coal stations and incinertors even roasting meat
what did hill state about PAHs in 1761?
that users of snuff has a high incidence of nasal pollups
what did pott state in 1775 about PAHs?
chimney sweepers had a high incidence of scrotal cancer due to soot
what did Rehn state in 1895 about PAHs?
there was a high incidence of skin cancer in coal tar industry
what did yamagiwa and ichikawa state about PAHs in 1915?
they were the first to demonstrate chemical carcinogenesis
what did kennaway et al demonstrate in 1933?
isolated 3,4-benzopyrene which is the principle carcinogenic substance of coal tar
why dont PAHs undergo biomagnification ?
because they can undergo photodegradatio and becausse many organisms have evoled detoxification enzymes
what shape molecule is the phenanthrene nucleus and what does this enable ?
its a planar molecule
- enables binding to DNA - intercalation between base pairs
what is the phenanthrene nucleus made up of?
3 fused rings
- more consituents can be added and this increases carcinogenicity
what are the 3 regions of the phenanthrene nucleus ?
bay region= has to be free of constituents
k region= double bond that has a higher electron density than the other double bonds in the molecule
convex edge= has to be free of constituents
what was pullmans electronic theory ?
early 1950s
the french chemists were interested in the distribution of electrons and how this affects carcinogenicity
- found an association between electron density and the K region
- then found the L region which has poor electron density and thought it was the balance between the K and L region
- then they found the m region and then it was thought that carcinogenicity was affected by all 3 regions
after the electronic theory what was discovered about the carcinogenicity of PAHs?
it was discovered that the carcinogenic compound was not the parent commpound but the carcinogens are derived from it
what can happen to 3,4-benzopyrene when its metabolised?
undergo oxidation by cytochrome P450s 1A1/1A2/1B1- expoxiation of the K region
this causes the K region epoxides to be able to covalently bond to DNA
produces 4,5-arene oxide K region epoxide- this is the chemically reactive part
what can make the 4,5-arene oxide K region epoxide more excretable ?
reacting it with epoxide hydrolase to produce 4,5-trans diol which readily conjugates with glucuronic acid
- this makes it more water soluble so more excretable
what is a key factor for benzopyrene to be carcinogenic ?
it has to undergo biotransformation and carcinogenicity is only seen when its bound to DNA not when its bound to RNA or proteins
what are the 2 epoxide biotransformation pathways in mammals?
ISOMERIZATION
- produces a phenol formation
- these can form glucuronide and sulphate metabolites so they are very water soluble so readily excretable
GSH and GSTs
- produces glutathione conjugate - this is readily excretable
what is the bulk of 3,4-benzopyrene epoxided into ?
98% to trans BP-7,8-dihydrodiol
how is 3,4-BP converted to trans BP-7,8-dihydrodiol?
3,4-BP converted to + and - BP-7,8-epoxide
the + BP-7,8-epoxide is converted to +BP-7,8-dihydrodiol by mEH
what is trans BP-7,8-hydrodiol?
its a proximate carcinogen- its on its way to ultimate carcinogen
- it undergoes greater covalent bonding to DNA compared to 3,4-BP
what happens to - BP-7,8-dihydrodiol?
it undergoes further epoxidation across 9,10 carbon atoms and this leads to the production of 9 bay region epoxide
- this has 2 formations= - syn-BP-7,8-diol-9,10-epoxide and + anti-BP-7,8-diol-9,10-epoxide
what is the ultimate carcinogen ?
+ anti-BP-7,8-diol-9,10-epoxide
its the trans isomer because one oxygen atoms projects up while the other projects dow
it can induce mutagenesis
what does the formation of epoxides in the bay region encourage ?
encourages formation of a carbonium ion
- this occurs because there is a slight dipole in the epoxide ring
where does the carbon atom of carbonium ion normally binds ?
it is electron deficient so it binds to guanine group of DNA to the exocyctic NH2 - can also bind to N7 of guanine
what is ARNT ?
aryl hydrocarbon receptor nucleus translocator
what are PAHs able to do ?
they can increase their own rate of metabolism and this increase the likelihood of the production of the ultimate carcinogen
what do PAHs do in the cytoplasm ?
binds to AhR and this causes it to migrate into the nucleus
chaperone proteins associate with the PAH-AhR complex
this complex binds to ARNT and this heterodimer then binds to various promoter sites
this causes increased expression of the gene
increases the synthesis of cytochrome 1A1, 1A2, 1B1
