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Chemical Carcinogenesis

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Gu YZ, Hogenesch JB, Bradfield CA The PAS superfamily: ... SARs- PAH. 3-methylcholanthrene (3MC) is a PAH. Induces AHH (CYP1A1) TCDD and 3MC in rat liver ... – 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/cancer/pharm1.ppt
  • http//dmg.nott.ac.uk/teaching/cancer/
  • Poland and Knutson Annu. Rev. Pharmacol. Toxicol.
    22 517-554
  • Gu YZ, Hogenesch JB, Bradfield CA The PAS
    superfamily Sensors of environmental and
    developmental signals ANNU REV PHARMACOL 40
    519-561 2000

2
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
3
Causes of cancer
Note that diet, tobacco, occupation, alcohol and
pollution are principally chemically-induced
cancers.
4
Screening for carcinogens
  • Animal tests
  • 50 animals per group
  • Maximal tolerated dose (MTD), and 25
  • Cost 250 000
  • Time 2 years (rat or mouse)

5
Problems with bioassay
  • The US National Toxicology Programme has tested gt
    500 compounds, with selection based solely on
    environmental relevance
  • Approx 59 of all chemicals cause cancer
  • Food 1000s of chemicals

6
Genotoxins vs non-genotoxins
  • Mutagenic (genotoxic) carcinogens can be easily
    detected (e.g. Ames test)
  • Non-genotoxic carcinogens account for 30-50 of
    rodent bioassay carcinogens
  • No clear test for non-genotoxins
  • Consequences for development of pharmaceuticals

7
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)
8
TCDD is a potent toxin
  • LD50 values
  • 1mg/kg guinea pig
  • 20-50mg/kg rat
  • 70mg/kg monkey
  • 5000mg/kg hamster
  • Highly toxic in chicken, fish
  • Lethality involves a wasting syndrome,
    involving many bodily organs, and taking 2-4 weeks

9
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

10
A prototypical non-genotoxin
  • TCDD is a potent carcinogen
  • Very weak/ no mutagenicity in Ames test
  • No activity in tests of DNA damage
  • 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

11
TCDD is a tumour promoter
DEN
Vehicle control- 6 months
0 tumours
DEN
TCDD- 6 months
5/7 tumours
TCDD- 6 months
0 tumours
12
History of TCDD
  • 1976 Seveso (http//www.roche.com/roche/about/esev
    esa.htm)
  • A reaction vessel containing trichlorophenol
    overheated, and exploded. The resulting TCDD
    contamination (gt100g) led to the evacuation of
    people over a wide area.
  • 1999 Belgium
  • Chick edema disease- contaminated chicken
    foodstuffs

13
Pleiotropic response
  • Induction of
  • cytochromes P450 1A1, 1A2 and 1B1
  • CYP1A1 is known as aryl hydrocarbon hydroxylase
    (AHH)
  • all three P450s are potent in the metabolism of
    aromatic hydrocarbons
  • UPDGT
  • GST

14
Related chemicals
Cl
Cl
Cl
Cl
  • Chlorinated dibenzofurans
  • Chlorinated biphenyls
  • Chlorinated naphthalenes
  • Polycyclic Aromatic Hydrocarbons
  • Similar effects
  • Less potent
  • Same pleiotropic response

O
15
Structure-Activity Relationships
  • The ED50 for induction of AHH in chick embryo is
    0.3 nmol/kg with TCDD
  • 15 different halogenated DbDs showed an SAR for
    induction of AHH
  • gt 3 Cl
  • Occupy 2,3,7,8 positions
  • gt1 ring position unsubstituted
  • Correlation between potency for inducing AHH and
    toxicity

16
SARs- PAH
  • 3-methylcholanthrene (3MC) is a PAH
  • Induces AHH (CYP1A1)
  • TCDD and 3MC in rat liver
  • Produce similar maximal induction response for
    AHH
  • Administration of both compounds produces no
    additive effect
  • Parallel dose-response curves
  • TCDD 30,000 times more potent (ED50 0.8
    nmol/kg)

17
A genetic locus in mice
  • PAHs induce AHH (ie P450) in the skin (and liver)
    of mice
  • But there is genetic variation
  • DBA/2 mice do not induce with 3MC
  • C57Bl/6J mice do induce with 3MC
  • Responsiveness maps as an autosomal dominant
    between C57 and DBA
  • the Ah locus (Aryl Hydrocarbon)
  • TCDD induces in all mice strains

18
Ah locus
  • Two possibilities
  • (a) 3MC, TCDD have distinct receptors
  • (b) the same receptor
  • Dose response for TCDD in responsive and
    non-responsive strains
  • The dose of TCDD required for induction is
    10-fold greater in non-responsive strains of mice

19
Ah Locus
  • AHH responsive mice are about 10-fold more
    sensitive than non-responsive mice to
  • Thymic involution
  • Hepatic porphyria
  • Teratogenesis
  • The Ah locus controls toxicity
  • How does Ah work ?

20
Ah encodes a receptor
  • Receptor identified in the liver cytosol of
    C57Bl/6 mice
  • High affinity 0.2 nMolar
  • 8 pMols receptor/ gm liver
  • 50 000 molecules/ liver cell
  • Lower affinity receptor in DBA/2 mice
  • Correlation between ability to bind various
    compounds and potency for induction

21
Ah Receptor
  • Human AhR is 96 kDa
  • Binds dioxin directly
  • Family of cellular signalling receptors

1
805
228
416
HLH
PAS1
PAS2
Transactivation
Ligand-Binding Domain 190 amino acids, 25 kDa
22
AhR and dioxin signalling
TCDD
Arnt
AhR
Transcription
hsp90
23
AhR -/- mice
  • Transgenic mice without AhR gene
  • Unable to induce cytochrome P450 by TCDD, PAH
  • TCDD toxicity vastly reduced (gt100 fold)
  • Greatly reduced tumour incidence in skin after
    application of Benzo(a)Pyrene
  • Due to AhR
  • Or to lack of induction of cytochrome P450 ?
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