Genotoxic compounds. CHE Chapter 8. FM Chapter 4.8
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1 Genotoxic compounds CHE Chapter 8 FM Chapter 4.8
2 Gene regulation
3 Cancer; something wrong with the genes... can be reparied!
4 Repairing genes in principle perfect
5 Repairing genes "error prone"
6 Reactions with electrophiles Adenin Guanin Cytosin Important Dominant Uracil...sulfated metabolites...nitrite
7 Cross-linking of DNA
8 DNA-bases are easily destabilised
9 Intercalation
10 Intercalation
11 Mutations classes 1. Point mutations: -base pair substitutions -frame shift mutations 2. Chromosome mutations
12 Base pair substitution a limited damage
13 Frame shift mutation more serious
14 Frame shift mutation A possible mechanism
15 Chromosome mutations Loss of DNA Move of DNA Serious for the cell
16 Chromosome mutations Loss of DNA Move of DNA Serious for the cell Extra chromosome 21: Down s syndrom
17 Effects of different mutations Positive improved survival (evolution!) Neutral no change in function Silent on inactive genes Negative decreased function Lethal cell death
18 Effects of different mutations
19 50% of all pregnancies? Effects of different mutations
20 Carcinogenic compounds Chemical carcinogenesis Effects on cell division: cell loses control over cell division Carcinogenic: transforms cell into cancer cell
21 Carcinogenic compounds Chemical carcinogenesis Tumors Benign ( friendly ) Malign ( bad ) Cancers Carcinoma (epithelia) Sarcoma (connective tissue) Myeloma (plasma cells) Melanoma (melanocytes) Leukemia (leucocytes)
22 Classical definition of chemical carcinogens Uncontrolled cell division No apoptosis Mutates/ adaptive
23 Carcinogenic compounds Chemical carcinogenesis Carcinogenesis causes/agents: spontaneous (evolution!) chemicals physical (electromagnetic radiation) viruses (bacteria)
24 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
25 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
26 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
27 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
28 Cancer causing external factors Tobacco 30 % Alcoholic beverages 3 Food 35 Workplace environment 4 Env. pollutants 2 Pharmaceuticals 1 Geophysical factors 3 Infections 10?
29 Cancer causing external factors Latency time...
30 Cancer causing external factors in food...and nitrite.
31 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 damages/cell/day/repaired Modulates transcription Mitogenes Cocarcinogenes and promotors Immunosuppressive compounds Hormones
32 Chemical carcinogenes All chemicals are mitogenic at high enough concentrations (tissue grows) Are animal experiments with high concentrations relevant?
33 Chemical carcinogenes Natural Synthetic? Ca 50% of all chemicals turn up positive in Ames test...
34 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.
35 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)
36 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
37 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...
38 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
39 Antioncogenes:
40 Antioncogenes:
Mutations: 2 general ways to alter DNA. Mutations. What is a mutation? Mutations are rare. Changes in a single DNA base. Change a single DNA base
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