Mutagens

1. MUTAGENS DR RITESH SHIWAKOTI MScD PROSTHODONTICS PHYSIOLOGIC CHEMISTRY

2. Mutagens Mutagens are substances that change the genetic information of an organism, usually by changing DNA. Mutagens are usually also carcinogens as mutations often cause cancer. Common mutagens include ethidium bromide, formaldehyde, dioxane , and nicotine . Mutation is replacement of nitrogen base with another in one or both the strands or adition or delation of a base pair in a DNA molecule.

3. Mutagenicity: Refers to induction of permanent changes in the information content of genetic material. Discovery of mutagenesis: In the 1920s, Hermann Muller discovered that  x-rays caused mutations in fruit flies . He went on to use x-rays to create Drosophila mutants that he used in his studies of genetics . He also discovered that x-rays not only mutate genes in fruit flies but also have effects on the genetic makeup of humans.

4. Basic structure of DNA: Backbone made of sugar and phosphate s groups joined by phospho-diester bonds. bonds.

5. Sources for mutation :

6. Types of mutagens: Chemical Alkylating agents Base analogs Methylating agents DNA intercalating agent Reactive oxygen species UV radiation Ionizing radiation

7. Alkylating agents Alkyl-group on DNA -----> crosslinking G in DNA.

8. Classical alkylating agents Nitrogen mustards Cyclophosphamide Mechlorethamine or mustine Uracil mustard Melphalan Chlorambucil Ifosfamide Nitrosoureas Carmustine , Lomustine and streptozocin Alkyl sulfonates = Busulfan

9. Base analogs These chemicals structurally resemble purines and pyrimidines and may be incorporated into DNA in place of the normal bases during DNA replication: bromouracil (BU)-- artaificially created compound extensively used in research. Resembles thymine (has Br atom instead of methyl group) and will be incorporated into DNA and pair with A like thymine. It has a higher likelihood for tautomerization to the enol form (BU *) aminopurine --adenine analog which can pair with T or (less well) with C; causes A:T to G:C or G:C to A:T transitions. Base analogs cause transitions, as do spontaneous tautomerization events.

10. Intercalating agents Acridine orange, proflavin , ethidium bromide (used in labs as dyes and mutagens ) All are flat, multiple ring molecules which interact with bases of DNA and insert between them . This insertion causes a "stretching" of the DNA duplex and the DNA polymerase is "fooled" into inserting an extra base opposite an intercalated molecule. The result is that intercalating agents cause frameshifts .

11. Some of DNA intercalating agents Berberine Ethidiun bromide Proflavine Daunomycin Doxorubicin Thalidomide

12. Agents altering DNA structure -- large molecules which bind to bases in DNA and cause them to be noncoding--we refer to these as "bulky" lesions ( eg . NAAAF) -- agents causing intra- and inter-strand crosslinks ( eg . psoralens --found in some vegetables and used in treatments of some skin conditions) -- chemicals causing DNA strand breaks ( eg . peroxides)

13. Radiation Radiation was the first mutagenic agent known; its effects on genes were first reported in the 1920's.

14. Ionizing radiation (X rays, gamma rays, UV light) causes the formation of ions that can react with nucleotides and the deoxyribose -phosphate backbone. Nucleotide excision repairs mutations

15. Ionizing Radiation: UV

16. AMES TEST Utilizes a histidine auxotroph of Salmonella determine if a chemical agent is a mutagen.  Spontaneous back mutations (a reversion back to the strain of Salmonella that can synthesize histidine ) is rare. Appearance of many colonies of the microbe on the minimal plate after the addition of the test chemical is an indication that the chemical is a mutagen

17. Some unusual mutations

18. Progeria It include rigid (sclerotic) skin,  full body  baldness (alopecia), bone abnormalities, growth impairment, and a sculptured nasal tip. It is caused by a mutation in the LMNA gene.

19.   Uner Tan Syndrome   Most obvious property is that people who suffer from it walk on all fours.

20.   Hypertrichosis or werewolf syndrome People with hypertrichosis have excessive hair on the shoulders, face, and ears. Studies have implicated it to a rearrangement of chromosome 8.

21. Epidermodysplasia Verruciformis G enetic disorder which makes people very prone to human papilloma virus. Wart like lesion appear all over body.

22. Severe Combined Immunodeficiency Disorder G ene disorder in which person is forced to live  in plastic isolation for fear of exposure to unfiltered air and the introduction of life-threatening pathogens . I t is the first genetic disease treated by gene therapy

23. Lesch–Nyhan Syndrome Affects 1 in 38 million Results in over production of uric acid in body Involuntary body movement Other symptoms like tensing muscles, jerking movements, and flailing limbs. Self-mutilating behaviours  are also common, including head banging , and lip and finger biting.

24. Ectrodactyly It is caused by several factors, including deletions, translocations, and inversions in chromosome 7 with split hand and split foot malformation.

25.  Proteus Syndrome The disorder results from a mutation in the AKT1 gene (which regulates cell growth ) It’s a condition in which bones, skin, and other tissues are overgrown