Genotoxic compounds

CHE
Chapter 8

FM
Chapter 4.8
Gene regulation
 Cancer;
“something wrong with the genes”...

can be reparied!
Repairing genes

in principle perfect…
Repairing genes

"error prone"
Reactions with Adenin Guanin

electrophiles
Important
Cytosin
Dominant
Uracil

....sulfated metabolites
...nitrite
Cross-linking of DNA
DNA-bases are easily destabilised
Intercalation
Intercalation
Mutations classes

1. Point mutations:
-base pair substitutions
-frame shift mutations

2. Chromosome mutations
Base pair substitution

a limited damage
Frame shift mutation

more
serious
Frame shift mutation

A possible
mechanism
Chromosome
mutations

Loss of DNA
Move of DNA

➡Serious for the

cell
 Chromosome
mutations

Loss of DNA
Move of DNA

➡Serious for the

cell

Extra chromosome 21:

Down’s syndrom
Effects of different mutations
Positive — improved survival (evolution!)

Neutral — no change in function

Silent — on inactive genes

Negative — decreased function

Lethal — cell death

Effects of different mutations
 Effects of different mutations

50% of all
pregnancies?
Carcinogenic compounds
Chemical carcinogenesis

Effects on cell division:

cell loses control over cell division

Carcinogenic:
transforms cell into cancer cell
 Carcinogenic compounds
Chemical carcinogenesis
Tumors

Benign (“friendly”) Malign (“bad”)

Cancers
Carcinoma (epithelia)
Sarcoma (connective tissue)
Myeloma (plasma cells)
Melanoma (melanocytes)
Leukemia (leucocytes)
 Classical definition of chemical carcinogens

Uncontrolled cell division

No apoptosis
Mutates/”adaptive”
Carcinogenic compounds
Chemical carcinogenesis
Carcinogenesis causes/agents:
• spontaneous (evolution!)
• chemicals
• physical (electromagnetic radiation)
• viruses
• (bacteria)
Does chemicals cause cancer?

Animal experiments
Epidemiological investigations, compare exposed
populations with control populations
Comparison between countries
Emigrant studies

Ca 80 % of human tumors depend on surrounding

factors, primarily chemical ones
 Does chemicals cause cancer?

Chemical

Organ affected

Activity

Aromatic amines

Bladder


Dyes
Benzidine





Rubber
4-Aminodiphenyl
2-Naphthylamine
Arsenic


Skin, lung


Metal manufacturing
Asbest



Lung


Isolation
Benzene


Bone marrow
Glue
Bischloromethylether
Lung


Ion exchange supports
Cadmium

Prostate
Pigment manufacturing
Cromium


Lung

Pigment manufacturing
Nickel


Nose, lung
Nickelfactory
Mustard gas

Throat, lung

Chemical weapon manufacturing
Vinyl chloride
Liver

PVC-manufacturing
 Does chemicals cause cancer?

Organ affected

High risk area

Low risk area
Ratio

Throat


Iran



Nigeria



300
Skin




Australia


India



200
Liver




Mozambique


England


100
Lung




England



Nigeria



35
Stomach


Japan




Uganda



25
Colon


Denmark



Nigeria



20
 Does chemicals cause cancer?
Compare tumor occurance in japanese, japanese immigrants in
USA and caucasian americans.
Organ


Japaner
gen. 1
gen. 2
gen. 3

Caucasians

Stomach


++++

+++
++
+


+
Colon
+


+++
++++ +++

++++
Breast

+


+
++

++++


++++
Prostate

+


+

+

+++


++++
Cancer causing external factors

Tobacco 30
%
Alcoholic beverages
3
Food
35
Workplace environment
4
Env. pollutants
2
Pharmaceuticals
1
Geophysical factors
3
Infections
10
?
Cancer causing
external factors

Latency time...
Cancer causing external factors in food

...and nitrite.
 Chemical carcinogenes
Reactive compounds (before or after metabolism) that cause mutations: Genotoxic carcinogenes

Electrofiles (most classified compounds)

Radicals or reactive products formed in radicalreactions
Metal ions

Chemicals indirectly affecting DNA: epigenic carcinogenes

Enzym inhibitors Ca 10000 damages/cell/day/repaired

Modulates transcription
Mitogenes
Cocarcinogenes and promotors
Immunosuppressive compounds
Hormones
 Chemical carcinogenes

All chemicals are mitogenic at high enough concentrations (tissue

grows)

Are animal experiments with high concentrations relevant?

 Chemical carcinogenes

Natural — Synthetic?

Ca 50% of all chemicals turn up positive in Ames test....

Oncogenes, protooncogenes and
antioncogenes
Oncogenes are individual genes that, when introduces in
healthy cells, make the cell loose control over cell
division

Many oncogenes are identified, most from carcinogenic

viruses

Protooncogenes are exact (almost) copies of oncogenes,

present in all of our cells. They normally carefully regulate
and code for proteins stimulating cell division.

Antioncogenes are genes coding for proteins inhibiting

cell division.
 Oncogenes’ proteins

Protein kinases,
Enzymes that phosphorylates other proteins (e.g.
tyrosin), which strongly affect the proteins’ functions.

I.e. activation of an oncogene can induce many new

properties of the cell

Growth factors,
Proteins stimulating cell division (normally expressed
e.g. platelets in injured tissue)
From protooncogen to oncogen

Protooncogener can be activated into oncogenes by:

Point mutations in a protooncogen or in genes

involved in their regulation

Chromosome mutations moving a protooncogene

from an inactive part to an active part of the genome
From protooncogen to oncogen
The oncogene causing uncontrolled cell division in a human urinary bladder
tumor differed only in one DNA-base from the protooncogene in healthy cells

i.e. only one base pair substitution...

 Antioncogenes can be inactivated by:

Point mutations in an antioncogene or in genes

regulating it

Chromosome mutations moving an antioncogene

from an active to an inacive part of the genome
Antioncogenes:
Antioncogenes: