Carcinogens Flashcards
what percentage of cancers are caused by environmental causes
80%
what are the 5 groups of carcinogens
alkylating agents aromatic amines azo dyes nitroso compounds polycyclic aromatic hydrocarbons
what are the specific types of environmental causes of cancer
toxins
UV/ionising radiation
oncogenic viruses
man-made carcinogens
how many forms of PAHs are produced and how
700 by conbustion of hydrocarbons
how are we exposed to pahs
diet, inhilation, lipophilic absorption through skin
why do pahs bioaccumulate but not biomagnify
due to enzymatic detoxification
why is persistence of pahs limited
photodegradation
what was the first pah to be discovered
3,4-benzopyrene
what is the structural simalarity between the most potent chemicals
phenanthrene nucleus
what is the K region of the phenanthrene ring
the area of highest electron density
what property of the K ring allows interaction with DNA
planar
what name is 3,4-benzopyrene also known by
benzo-a-pyrene
what did pullmans electronic theory (1950) show
link between K region and carcinogenicity
what was thought to be important in carcinogenicity and what was proven otherwise
L:K:M balance of electron densities
found its actually the active metabolites which are carcinogenic
who first observed that the metabolites were in fact the carcinogens by putting benzopyrene but not the parent compounds on mice skin
elizabeth miller (1950s)
who linked DNA binding to carcinogenicity and in which decade
Brooks and Lawley 1960s
which cytochromes produce 7,8-epoxides of the K region
chytochromes p450 1A1 1A2 1B1
what are the three methods of epoxide degradation
hydrolases convert it to a trans7,8- diol
glutathione peptide conjucation
spontaneous isomerisation to phenols
what percentage of k region epoxides are left after to bind to DNA
5%
are diol products more or less toxic
more
which trans-diol epoxide was found to bind DNA to a greater extent than 3,4-benzpyrene
7,8-dihydrodiol
what percentage of epoxides form above the ring (+ enantomer)
98%
what is Cyt p450 also known as
CYPs
what is the 7,8-diol produced by the mitochondiral epoxide hydrolase next converted to
7,8-diol-9,10-epoxide
which form + or - is the diol in
-
which enatomer is thought to be the ultimate carcinogen
the (+) 7,8-diol-9,10-epoxide
whih residue to the diol epoxides mainly bind
guanine
why will the epoxide ring open to form an electrophilic carbinium ion at C10
the ring is strained
which atom does the epoxide bind
NH2 amine or N7
what 4 step do pahs increase their metabolism
bind aryl hydrocarbon receptor in cytoplasm
transported to nucleus using chaperones
binds ARNuclear transporter heterodimer to bind to gene promoters
increases synthesis of CYPs 1A1 1A2 1B1
how does PAH binding cause carcinogenicity
causes damage to dna, repair not always acurate
what are the critical genes in which mutations occur
proto onco genes (ras) and tumour supressor genes (p53)
what percentage of tumours are caused by ras mutations
10
which group of proteins do ras genes encode
p21
what has been lost from oncogenic p21 and what is the resut
GTPase activity
constantly activated
what is the role of p53
accumulates around damaged dna to allow repair to occur
induces apoptosis if repair fails
what effect does muttion often have on p53
inactivation
what can affect susceptibility to chemical carcinogens
expression of enzymes involved in metabolism of carcinogens
mutations in enzymes involved in metabolism
efficiency of dna repair
what is usually the target organ of PAHs
liver
what can be used as biomarkers of pah exposure
binding of electrophilic metabolites to proteins and dna
what can be used to assay pah exposure
haemoglobin and albumin
what are the effects of pahs aside from cancer
phototoxicity
cardiovascular disease (atherosclerosis)
foetal malformations
disruption of development 3-6 years
what are the adverse affects which arent cancer caused by
activation of aryl-carbon receptor
how is damage to DNA detected
distortion of helix
what isthe general process of dna repair
xp proteins provide scaffold, helicase unwinds dna, incisions by exonucleases remoce 27-29bp, dna polymerase delta and epsalon extends dna with high fidelity, dna ligase joins bases together
under what circumstances are mismatches in dna not recognised and why
durin cell replication
uses low fidelity polymerase
what is the common mutation caused by 3,4benzopyryne damage
g to t
what is the common mutation caused by uv damage
c to t
what are the 6 hallmarks of cancer
apoptosis evasion increased growth signals insensitivity to anti growth signals unlimited replication potential sustained angiogenesis tissue invasion and metastasis
why are most cancers found in eptithelial cells
most exposure and most repair and mutations
