Chemical carcinogens 1

Question 0

how many diagnoses of cancer are there each year ?

Answer 0

about 14 million

Question 1

what are the 5 main groups of chemical carcinogens ?

Answer 1

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

Question 2

how many people each year die from cancer ?

Answer 2

6-7 million

Question 3

how much of cancers have an environmental cause and what are they ?

Answer 3

80% 
exposure to radiation- UV and ionising
exposure to toxins 
exposure to oncogenic viruses 
exposure to man made carcinogenic materials

Question 4

what are polycyclic aromatic hydrocarbons ?

Answer 4

largest group of chemical carcinogens
several hundred chemically related compounds
consist largely of hydrogens are carbons

Question 5

why are PAHs ubiquitous ?

Answer 5

they are readily formed when organic material is combusted - forest fires, anthropogenic activity such as automobile engines, coal stations and incinertors even roasting meat

Question 6

what did hill state about PAHs in 1761?

Answer 6

that users of snuff has a high incidence of nasal pollups

Question 7

what did pott state in 1775 about PAHs?

Answer 7

chimney sweepers had a high incidence of scrotal cancer due to soot

Question 8

what did Rehn state in 1895 about PAHs?

Answer 8

there was a high incidence of skin cancer in coal tar industry

Question 9

what did yamagiwa and ichikawa state about PAHs in 1915?

Answer 9

they were the first to demonstrate chemical carcinogenesis

Question 10

what did kennaway et al demonstrate in 1933?

Answer 10

isolated 3,4-benzopyrene which is the principle carcinogenic substance of coal tar

Question 11

why dont PAHs undergo biomagnification ?

Answer 11

because they can undergo photodegradatio and becausse many organisms have evoled detoxification enzymes

Question 12

what shape molecule is the phenanthrene nucleus and what does this enable ?

Answer 12

its a planar molecule

- enables binding to DNA - intercalation between base pairs

Question 13

what is the phenanthrene nucleus made up of?

Answer 13

3 fused rings

- more consituents can be added and this increases carcinogenicity

Question 14

what are the 3 regions of the phenanthrene nucleus ?

Answer 14

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

Question 15

what was pullmans electronic theory ?

Answer 15

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

Question 16

after the electronic theory what was discovered about the carcinogenicity of PAHs?

Answer 16

it was discovered that the carcinogenic compound was not the parent commpound but the carcinogens are derived from it

Question 17

what can happen to 3,4-benzopyrene when its metabolised?

Answer 17

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

Question 18

what can make the 4,5-arene oxide K region epoxide more excretable ?

Answer 18

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

Question 19

what is a key factor for benzopyrene to be carcinogenic ?

Answer 19

it has to undergo biotransformation and carcinogenicity is only seen when its bound to DNA not when its bound to RNA or proteins

Question 20

what are the 2 epoxide biotransformation pathways in mammals?

Answer 20

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

Question 21

what is the bulk of 3,4-benzopyrene epoxided into ?

Answer 21

98% to trans BP-7,8-dihydrodiol

Question 22

how is 3,4-BP converted to trans BP-7,8-dihydrodiol?

Answer 22

3,4-BP converted to + and - BP-7,8-epoxide

the + BP-7,8-epoxide is converted to +BP-7,8-dihydrodiol by mEH

Question 23

what is trans BP-7,8-hydrodiol?

Answer 23

its a proximate carcinogen- its on its way to ultimate carcinogen
- it undergoes greater covalent bonding to DNA compared to 3,4-BP

Question 24

what happens to - BP-7,8-dihydrodiol?

Answer 24

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

Question 25

what is the ultimate carcinogen ?

Answer 25

+ 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

Question 26

what does the formation of epoxides in the bay region encourage ?

Answer 26

encourages formation of a carbonium ion

- this occurs because there is a slight dipole in the epoxide ring

Question 27

where does the carbon atom of carbonium ion normally binds ?

Answer 27

it is electron deficient so it binds to guanine group of DNA to the exocyctic NH2 - can also bind to N7 of guanine

Question 28

what is ARNT ?

Answer 28

aryl hydrocarbon receptor nucleus translocator

Question 29

what are PAHs able to do ?

Answer 29

they can increase their own rate of metabolism and this increase the likelihood of the production of the ultimate carcinogen

Question 30

what do PAHs do in the cytoplasm ?

Answer 30

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