Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
ChemicalandRadiationinduced
Carcinogenesis
2.8
2.9
2.10
Mar8&13,2007
Causes of cancer?
Causesofcancer
Physicalradiation
Chemicalchemicals
Biologicalmicroorganisms,especiallyviruses
2.8Specificchemicalagentscaninduce
cancer
[historicalperspectives]
Theevidencethatchemicalscaninducecancer
inhumanshasbeenaccumulatingformorethan
twocenturies.
Hill(1761)Nasalcancersoccurredinpeople
whousedsnuffexcessively.
Pott(1775)ahighincidenceofscrotal( )
skincanceramongmenwhohad
spenttheirchildhoodaschimney
sweeps
vonVolkman&Bell(~1875)
Skincancersoccurredinworkerswhoseskin
wasincontinuouscontactwithtar( )and
paraffinoils( ),(nowknownas
polycyclicaromatichydrocarbons,PAH)
Rehn(1895)
developmentofurinarybladdercancerin
aniline( )dyeworkers
Similar observations were later made in many
laboratories and established a relationship between
heavy exposure to 2-naphthylamine, benzidine, or
4-amino-biphenyl and bladder cancer.
Yamagiwa
Direct evidence for a carcinogenic effect
of the polycyclic aromatic hydrocarbons in
tars (1930s):
Kennaway & Hieger synthetic 1,2,5,6-
dibenzanthracene was a
carcinogen.
Cook, Hewitt & Hieger identification of the
carcinogen 3,4-
benzpyrene in coal tar
Since 1940s, the list of known carcinogenic
chemicals has been expanded tremendously.
Carcinogenichydrocarbons
PAH
Chemical carcinogens: chemicals that cause tumor
formation
1. have a very broad range of structures with no
obvious unifying features
2. are genotoxic and can be classified into two
broad categories based on their action mechanisms:
a. Direct-acting carcinogens
- react with nitrogen and/or oxygen atoms in DNA
example: ethylmethane sulfonate (EMS)
b. Indirect-acting carcinogens
- become reactive after metabolic activation
examples: aflatoxin, benzo[a]pyrene
*genotoxic: an agent or process that interacts with cellular DNA,
resulting in alteration of DNA structure
Thedirectactingcarcinogensinteractwith
macromoleculesthroughthecovalentbond
formationbetweenanelectrophilicformofthe
carcinogenandthenucleophilicsitesinproteins
(e.g.,S,O,andNatomsincysteine,tyrosine,and
histidine,respectively)andnucleicacids(e.g.,N
andOatomsinpurineorpyrimidine),suchas
N-methyl-N-nitrosourea,achemically-reactive
alkylating agent.
Some agents can intercalate ( ) into the
DNA double helix by forming tight noncovalent
bonds (e.g., daunorubicin).
Most of carcinogens are indirectlyacting;
theydonotinteractinvitrowithmacro
moleculesuntilithasbeenincubatedwith
liverhomogenatesorlivermicrosomal
fractions.Thus,metabolicactivationof
certaincarcinogenicagentsisnecessary
toproducetheultimatecarcinogenthat
actuallyreactswithcrucialmoleculesin
targetcells.
Metabolic activation of benzo[a]pyrene
guanine
electrophilic
DNA
adducts
1. Cytochrome P450 catalyses initial epoxidation.
2. With the exception of the 1 - 2 and 2 - 3 oxides that convert to phenols, epoxide hydrolase may
catalyze the formation of dihydrodiols.
3. Benzo[a]pyrene-7, 8-dihydrodiol is further metabolized at the olefinic double bond by cytochrome
P450 to form a vicinal diol-epoxide (r7, t8-dihydroxy-c9, 10 epoxy-7,8,9,10-
tetrahydroxybenzo[a]pyrene).
4. The highly unstable arene ring opens spontaneously to form a carbocation.
5. This electrophilic species forms a covalent bond between the 10 position of the hydrocarbon and the
exocyclic amino group of deoxyguanosine.
Metabolicactivationofaflatoxin
epoxide
Aflatoxin B1, a toxin from a mold (Aspergillus flavus oryzae) that grows
on grain and peanuts when they are stored under humid tropical
conditions.
It is thought to be a contributory cause of liver cancer in the tropics.
DNA adduct formation
N7
O6
deoxyguanosine
a.Aninsertionoftheflatplanarringsof
apolycyclichydrocarbonbetweenthe
stackedbasesofdoublehelicalDNA
maydistortthehelix,leadingtoaframe
shiftmutationduringDNAreplication
pastthepointoftheintercalation.
b.AlkylatedbasesinDNAcanmispairwith
thewrongbaseduringDNAreplication
forexample,O6methyguaninepairswith
thymineinsteadofcytosineduringDNA
replication,leadingtoabasetransition
(i.e.,GCAT)typeofmutationduring
thenextroundofDNAreplication.
c. Many of the base adducts formed by
carcinogens involve modifications of
N-3 or N-7 positions on purines that
induce an instability in the glycosidic
bond between the purine base and
deoxyribose. This destabilized structure
can then undergo cleavage by DNA
glycosylase, resulting in loss of the base.
Purines and Pyrimidines
d. Interaction with some carcinogens has
been shown to favor a conformational
transition of DNA from its usual double-
helical B form to a Z-DNA form. This
could alter the transcribability of certain
genes, since BZ conformational
transitions are thought to be involved in
regulating chromatin structure.
Radiation-induced Carcinogenesis
Radiations contain energies greater than that
in chemical bonds. Therefore, chemical
bonds can be broken by radiation.
*HermannMuller(18901967),anAmericangeneticist,
receivedtheNobelPrizeinMedicine&Physiologyin1946.
The ability of radiation to cause human
cancer, especially leukemia, was dramatically
shown by the increased rates of leukemia
among survivors of the atomic bombs dropped
in World War II, and more recently by the
increase in skin cancer in individuals exposed
to too much sunlight (UV radiation).
UV radiation is a low-energy emission
and does not penetrate deeply. Hence, the
skin absorbs most of the radiation and is
the primary carcinogenic target.
A number of the points made about
chemical carcinogenesis are also true for
radiation-induced carcinogenesis. Both
x-rays and ultraviolet (UV) radiation cause
DNA damage.
When cells are exposed to UV light in
the 240- to 300-nm range, nucleic acid
bases acquire excited energy states,
producing photochemical reactions
between DNA bases. The principal
products in DNA at biologically relevant
doses of UV light are cyclobutane dimers
formed between two adjacent pyrimidine
bases in the DNA chain. Both thymine-
thymine and thymine-cytosine dimers are
formed.
Cyclobutane dimer
Ames test