carcinogens Flashcards
what are carcinogens?
chemical or physical sources that initiate or promote carcinogenesis
what is a DNA damage?
abnormal chemical structure in DNA which causes changes
what is a genotoxin?
a physical or chemical agent that can induce DNA damages
what is a mutation?
an alteration of the nucleotide sequence in the genome
what is a mutagen?
a physical or chemical agent that can induce mutations
what types of genotoxins are there? What do they cause?
Mutages (DNA adducts and mutations)
clastogens (chromosome breaks)
Aneugens (mitotic spindle)
what are the key characteristics of carcinogens?
is genotoxic
alters DNA repair
causes genomic instability
induces oxidative stres
induces chronic inflammation
is immunosuppressive
models receptor mediated effects
causes immortalization
alters cell proliferation/ cell death/ nutrient supply
what is the difference between genotixic carcinogens and non-genotoxic carcinogens?
genotoxic: initiate tumor formation by DNA damage and DNA mutagenesis. Is not concentration dependent. DNA damage is reversible but mutation is not. mutagenic
non-genotoxic: promote tumor formation by pathways other than DNA damage –> cell proliferation, cytotoxicity, hormonal effects
is concentration dependent, reversible and non-mutagenic –> provides growth advantage
Give examples for genotoxins and non-genotoxins
genotoxin: Aflatoxin B1, Formaldehyde, Nitrosamine, Vinyl Chloride
non-genotoxic: Asbestos, Dioxins, Estradiol, Phenobarbital
what are common types of DNA damage?
8-oxo-2’-deoxyguanosine: oxidative lesion in duplex DNA
ß-N-glycosidic bond between base and deoxyribose is hydrolyzed
Single Strand break: : directly or indirectly (BER)
double strand breaks
O6-MG: alkylation of oxygen antom of guanine –> repaired by suicide enzyme MGMT
spontaneous hydrolysis reaction of cytosine into Uracil
What is MGMT and how does it work?
is a suicide enzyme that is synthesized if DNA damage is detected: Transfers CH3 group of DNA to its self and is then degraded
how can genotoxic carcinogens be activated? what are direct and indirect genotoxins?
many genotoxins are not genotoxic by themselves but can form genotoxic metabolites through cellular metabolism: eg cytochrome P450 enzymes
direct genotoxins: active without metabolic activation
indirect: carcinogenic after metabolic activation
Procarcinogens are concerted by phase I enzymes. They then either form inactive metabolites which are secreted or ultimate carcinogens which are active and can lead to DNA damage
is DNA damage random?
No, each carcinogen has its specific pattern how it reacts with the DNA bases
how can DNA adducts be detected?
32P Postlabeling
Immunoassay
CG/MS and LC/MS
what is the relation between DNA damage, mutation and cell division?
cell division is required to fix a DNA damage
once a DNA damage is fixed in a mutation, it cannot be repaired