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Chemical Carcinogenesis

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Cause cancer in mouse, rat, monkey, guinea-pig, rabbit, fowl, newt, trout ... Tumorigenic in rat, mouse, guinea pig and fish (everything tested) ... – PowerPoint PPT presentation

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Title: Chemical Carcinogenesis


1
Chemical Carcinogenesis
  • David.bell_at_nottingham.ac.uk
  • http//dmg.nott.ac.uk/teaching/

2
Do chemicals cause cancer ?
  • Epidemiology
  • The study of illness in populations
  • Correlate with influences on the population, eg
    diet, work, geography
  • 1775
  • The surgeon, Percival Potts, noted that coal
    sweeps had a high incidence of cancer, scrotal
    cancer. He hypothesised that the cancer was due
    to their intimate and prolonged exposure to coal
    dust.

3
Latency
Cancer takes 10-50 years to develop in man
1900- Cigarette smoking an accepted habit
1940- rise in male lung cancer- alarm
1960- smoking is shown to be the cause of lung
cancer
1960-2000. People who started smoking before
1960 die of lung cancer Lung cancer is the most
frequent site of cancer in UK men
4
Causes of cancer
Note that diet, tobacco, occupation, alcohol and
pollution are principally chemically-induced
cancers.
5
Screening for carcinogens
  • Animal tests
  • 50 animals per group
  • Maximal tolerated dose (MTD), and 25
  • Cost 250 000
  • Time 2 years (rat or mouse)

6
Problems with bioassay
  • The US National Toxicology Programme has tested gt
    300 compounds, with selection based solely on
    environmental relevance
  • Approx 50-66 of all chemicals cause cancer

7
Nitrosamines
  • Cause cancer in mouse, rat, monkey, guinea-pig,
    rabbit, fowl, newt, trout
  • Wide range of organs affected
  • Formed in food in the presence of nitrate, and
    acid, ie pickles
  • Potent

R1
N
NO
R2
8
Nitrosamines
O-H
CH2
CH3
Oxidation
N
NO
N
NO
CH3
CH3
The methyl carbonium ion is a powerful
electrophile, and reacts quickly with
macromolecules.
H2-CO
CH3-NN-OH
N2
CH3-N2
CH3
OH-
9
Electrophiles
  • Chemical entities which react with centres having
    a surplus of electrons, or nucleo-philes.
  • Protein, RNA and DNA contain nucleophilic sites

10
Electrophiles and DNA 2
H
  • There are multiple reactions of electrophiles
    with DNA
  • O6 methyl guanine is promutagenic
  • The alkylated base mispairs G-T, instead of G C
  • This leads to inaccurate repair, and mutations in
    DNA
  • N7-G also promutagenic

N7
O
N
N
N
N
H2N
Guanine
dR
11
Genotoxicity
  • Toxicity to the genome- hence genotoxicity

12
Benzo(a)pyrene
1
Bay region
2
10
3
9
4
8
5
7
6
K region
High electron density at Bay and K regions Planar
molecule
13
Benzo(a)pyrene
  • Typical PAH
  • Ubiquitous
  • Coal tar, organic matter
  • Formed during combustion of organics
  • Cooking !
  • Oils, especially used at high temperature
  • Chemically inert
  • Principal active agent in coal tar

14
B(a)P metabolism
Multiple sites of metabolism combination of
metabolism at multiple sites. Highly
complex metabolic pathways.
2
10
3
9
4
8
5
7
6
Hydroxylation- reactive phenols and quinones
15
The ultimate carcinogen
Cytochrome P450
O
B(a)P 7,8 epoxide
Epoxide hydrolase
P450
O
OH
OH
OH
OH
((anti))B(a)P 7,8 dihydrodiol 9,10 epoxide
B(a)P 7,8 dihydrodiol
16
Is BPDE important ?
  • Analysis of B(a)P- DNA adducts
  • BPDE should be more carcinogenic than BP
  • Dose mice at birth and autopsy at 7 months. Lung
    tumours/mouse are shown.

17
Adducts from B(a)P
  • Adducts form on C10- N2 of dG using the BPDE on
    DNA in vitro
  • The same adducts are formed in vivo on DNA
  • Mutations in the ras oncogene with BaP are
    typified by G-T transitions at codon 12 or 13

18
DNA repair
  • Methylnitrosourea (MNU) is a direct alkylating
    agent
  • In rats, it has tissue-specificity, with
    brain-specific tumorigenesis
  • DNA-adduct levels are similar in brain in liver
  • Adducts are removed rapidly in liver, but persist
    in brain

19
DNA damage ? cancer
DNA damage is similar between the two
strains Tumour development is markedly
different Therefore other factors control the
development of cancer
20
Do adducts cause cancer ?
  • Chemically synthesise DNA-adducts, insert into
    plasmid and transform into E. coli
  • Measure amount of mutations in prokaryotic DNA
  • Treat a cellular proto-oncogene with carcinogen
    in vitro
  • Transform DNA into cells, and look for cellular
    transformation

21
How many adducts for cancer ?
  • For a 50 incidence of tumours in rat liver
  • Estimate from 50 to 2000 adducts/ 108 nucleotides
    (2 per 100 000)
  • Variation
  • Measurement
  • Repair
  • Different compounds and adducts

22
The numbering of the beast
4
6
3
5
7
8
2
10
9
1
2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) One of
the most potent of a variety of related
compounds Long half-life in humans (6 years)
23
TCDD and cancer
  • Tumorigenic in rat, mouse, guinea pig and fish
    (everything tested)
  • Primate study aborted when total dose of 2 mg/kg
    lead to death
  • In rat, the lowest carcinogenic dose was 1.4
    ng/kg/day (Plt0.05) for thyroid tumours
  • MTD 71ng/kg/day

24
A prototypical non-genotoxin
  • TCDD is a potent carcinogen
  • Very weak/ no mutagenicity in Ames test
  • No activity in tests of initiation activity
  • Maximum estimate for binding of TCDD to rat liver
    DNA 1 molecule per 1011 bases
  • 1 per 107- 105 for known carcinogens
  • TCDD is a non-genotoxic carcinogen

25
Chemical carcinogenesis
  • Chemicals are involved in 60-80 of human cancers
  • Reaction of chemical with DNA
  • Some chemicals require metabolic activation
  • Non-genotoxic chemicals
  • Activation of cellular receptors
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