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
Chromoso
me
mutations

Loss of DNA
Move of DNA

➡Serious for
the cell
Chromoso
me
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: