the physical mutengens include:
- Uv light - ioniznzing radiation
causes: dimerisation of pyrimdide , hydration of cytosine and causses direct damage to the dna by the production of reactive oxygen species - x rays and gamma rays - travels through the cell without collisions and stand breaks if they collide w/ dna
- particle radiation as alpha and beta which impacts the nuclear dna and causes breaks in the dna
— are negative regulators of cell growth and commonly inactivated in cancer cells
tumor supressor
– found in normal cells and are involved in positive regulation of cell growth but are often mutated in cancer cells
proto-ongogenes
the process of carognsies involves:
1- initiation: genetic alteration or mutation of one or more cellular genes controlling the regulatory pathway
2- promotion: selective growth enhancement induced in the ignited checks and its progeny by the continuous exposure to the promoting agents
3- transformation : the preneoplastic cells transforms and expresses magian phenotype
4- progression : expression of malignant genotype and acquire aggressive characertsics as: genomic instability, uncontrolled growth, and metatsiss
—- are intrinsically reactive and form adducts with the dna without the metabolic modification
direct carigones
as: nitrogen mustard, methyl nitrosourea
—- require metabolic activation before damaging the dna by the covalent adduct formation or reactive oxygen species
procargones
becomes proximate carigoens and then ultimate cargoes which forms adducts as: benzo(a) pyrene , aflatoxin , dimethlnitroamine
mutegens and carcinogens causes damage to the dna by :
1- covalent adduct formation as:
- alkylation
- deamination
- formation of bulky aromatic type
- dimerisation
2- oxidative damage
in bulky aromatic adducts:
the first chemically identified carcinogens were —
- polycyclic aromatic hydrocarbons
- they are very common envriomental contaminants
- number o fused bene rings ( CHECK STRUCTURE )
- formed by the incomplete combustion of fossil fuel ad vegetable matter
- chemically inert so it require metabolic activation by cytochrome P450
- example of the bulky aromatic: bees(a) pyrene
activation of benzodiazepines(a)Byrne and adduct formation
1 – BP is converted to Benzo(a)pyrene-7,8-diol by P450 and Epoxide hydrolase
2 – P450 adds another epoxide group to positions 9,10.
3 – Diol epoxide can undergo cleavage of C-O bond of epoxide at position 10 and form carbocation intermediate (electrophile)
4 – Ultimate carcinogen targets N-2 deoxyguanine residues which can perform nucleophilic attack of carbocation
Aflatoxin B1 targets —-
- N7 on guanine
- found in soil and decay vegetation
-can contaminate food sources - leads to liver cancer
-Procarcinogen Aflatoxin B1 epoxide (ultimate carcinogen).
Targets N7 nitrogen in guanine when forming adduct
— attaches small alkyl groups into the nucleophilic sites to form dna adducts as dimethylnitroamines and nitrosamines
- alkylating agents
Dimethylnitrosamine and other nitrosamines are products of —- and are examples of —- they are procarogenes which produces —-
- industrial bi-products and tobacco smoke and cured meat
- alkylating agents
- reactive diazonium and carbonic ions
nitrous acid HNO2 is a —- which converts cytosine into – and adenine into — and guanine into —
the hydrogen bonding potential of modified bases is altered resulting in —-
hypoxathine can pair with – and causes mismatch
- demainating agent
- auricle
- hypoxanthine
- xanthine
- mismatch
- cytosine
— is the Removal of errors due to adduct and oxidative damage
excesion repair
is the removal of deamination and small deletion & insertion damage
mismatch repair
Removal of methyl groups from bases without removal of base is
direct reversal repair
Removes a variety of base damages such as 8-oxo-guanine, deaminated bases and methylated bases.
- base excision repair
- 8-oxo-gunaine is from reactive oxygen species and is repaired by dna glycolyses as it flipped out of the double helix and cleaveged into the n-glycosidic bond and creates an absasic site
Repairs DNA with bulky adducts
Adducts result from UV damage or electrophilic aromatic mutagens such as Benzo(a)pyrene —
nucleotide excision repair
( Recognition of the damage initiates removal of a short single-stranded DNA segment containing damage.
The undamaged complementary strand is left intact
DNA polymerasecomplementary strand used as a template to synthesize replacement sequence.
DNA ligase completes repair process.)
