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Activation of carcinogens

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Mutations in the ras oncogene with BaP are typified by G-T transitions at codon 12 or 13 ... Unusually, these cluster at codon 249 ... – PowerPoint PPT presentation

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Title: Activation of carcinogens


1
Activation of carcinogens
  • Chemicals, Risk Cancer 3
  • David R. Bell
  • Molecular Toxicology David Josephy 0-19-509340-2

2
Coal tar
  • Coal tar, coal dust, and some petroleum oils are
    highly carcinogenic
  • Percival Potts and coal sweeps
  • Use animal bioassay to separate the active
    ingredients
  • Principally high molecular weight hydrocarbons
    with multiple rings (polycyclic aromatic
    hydrocarbons)- which are not reactive

3
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
4
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

5
B(a)P- an electrophile
  • The Millers thought that BaP must form an
    intermediate electrophile
  • PAHs often become fluorescent after reaction
  • Carcinogens bind to proteins in target organs to
    produce fluorescent protein adducts
  • Also bind to DNA
  • Formation of an Ultimate Carcinogen, which is an
    electrophilic metabolite of the parent compound
  • Ca. 1950

6
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
7
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
8
The electrophile
OH

OH
OH
Cation at C10 is stabilised by the high electron
density in the bay region
9
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.

10
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

11
BaP adducts and smoking
  • Look at population of controls and smokers
  • Look at incidence of BaP adducts and cancer
  • What is the relative risk of getting cancer if
    you have BaP adducts ?

12
Aromatic amines
  • Used extensively as dyes, and in chemical
    processes
  • Azo dyes metabolised to aromatic amines
  • Epidemiological detection of bladder cancer in
    occupationally-exposed population

13
Aromatic amines
NH2
NH2
NH2
benzidine
1-napthylamine
CH3
CO
NH
NH2
2-napthylamine
2-acetylaminofluorene (AAF)
14
2-AAF activation
Ring hydroxylation detoxification
CH3
CO
P450
NH
CH3
P450
CO
CH3
N
CO
Nitrenium cation
N-OH
CH3
Sulfo- transferase
CO
N-OSO3H
15
Popular world cancers
  • Liver cancer shows high incidence in tropical
    regions
  • 1.5 per 105 in Australia
  • 22 per 105 in East Africa
  • Disease of younger people

16
Causes of liver cancer
  • Hepatitis viruses (B)
  • Fungal contamination of food
  • Aspergillus flavus produce aflatoxins
  • Highly potent liver toxins
  • Liver carcinogens

17
Aflatoxin B1
Potent liver toxins excess aflatoxin leads to
liver necrosis. Liver carcinogens detect
as urinary DNA-aflatoxin, or in DNA or protein
adducts. Form N2-dG adduct
O
O
P450
O
O
H
OCH3
O
O
18
Epidemiology
  • People with HBV infection have a greater chance
    of HCC
  • People with urinary aflatoxin metabolites have a
    greater chance of HCC
  • People with both HBV and urinary aflatoxin
    metabolites have a much greater chance of HCC

19
p53 mutations
  • Hepatocellular carcinoma has a high incidence of
    p53 mutations
  • Unusually, these cluster at codon 249
  • Mutations at 249 arise from a G-T transition,
    typical of aflatoxin adducts

20
Activation of carcinogens
  • Many important carcinogens require metabolic
    activation
  • Multiple enzyme systems involved in activation
  • Linkage from
  • Chemical activation
  • Adducts
  • Specific mutations
  • Cancer
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