Radiation And Chemical Carcinogens: Genetic Predisposition To Neoplasia

Question 0

UV and skin cancer

Answer 0

Squamous and basal cell carcinoma are limited almost exclusively to sun exposed areas of white skinned people
More frequent in high UV areas
More frequent in out door workers
Can cause skin cancer in animals

Question 1

Effects of radiation on DNA

Answer 1

Direct-> depends on energy of radiation
-> excitation and ionisation of electrons to produce ions
Or
-> dimerisation of pyramiding nucleotides by UV
Indirect-> free radical formation

Question 2

Xeroderma pigmentosum

Answer 2

Autosomal recessive disease
Unusual erythmal response to sunlight-> becomes red quickly
Excessive freckle formation
Pigmentation abnormalities
Much more sensitive to UV than normal cells-> lack the ability to repair damaged DNA or can’t repair as rapidly -> can repair broken strands but lack the endonucleases required to make incisions in DNA to remove the dimer before the gap is filled by DNA polymerase
In X-ray damage the hole has already been made

Question 3

Why does xerodema pigmentosum cause skin cancer

Answer 3

Lack ability to remove T-T diners rapidly

• > DNA polymerase doesn’t know how to proceed in replication so leaves gaps in the new DNA
• > induces a DNA repair system-> SOS repair-> less accurate-> more chance of errors-> increased chance of mutation in oncogene or tumour supressor region

Question 4

Chemical carcinogens

Answer 4

Polycyclic aromatic hydrocarbons-> benze’s
Azo dyes
Nitrosamines
Acetoaminofluorene
Asbestos-> irritation of lung tissue-> increased cell division

Question 5

Polycyclic aromatic hydrocarbons

Answer 5

Specific mixed function oxidises are responsible for metabolising PAH’s
->Aryl hydrocarbon hydroxylase AHH
Inducible by its substrates-> not readily made
When you inhale cigarette smoke or car fumes-> induce AHH synthesis
Level of induction is genetically controlled-> low, intermediate and high inducers-> most people are low

Question 6

Benzo[a]pyrene metabolism

Answer 6

Member of PAH family
AHH in conjunction with other enzymes tries to remove BP-> produce a highly carcinogenic form of BP
This can either be detoxified by glutathione transferase, UPP glucuranyl transferase, sulphotransferase
or attached by electron rich atoms in molecules like guanine in DNA to form a covalent bond

Question 7

BP metabolism and cancer

Answer 7

Detoxification pathway can become saturated-> more likely to happen in high inducers-> more likely to get cancer
Either by
-> causing incorrect base pairing when DNA replicates-> GT base pairs form as BP is occupying one of the H bonding positions on G-> might cause cancer if in oncogene or TS
-> similar to UV light-> induces the less accurate SOS repair system to remove BP and consequently inserts cancerous mutations