MUTAGENSDR RITESH SHIWAKOTI

MScD PROSTHODONTICS

PHYSIOLOGIC CHEMISTRY

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.

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.

Basic structure of DNA:

Backbone made of sugar and phosphates groups joined by phospho-diester bonds.bonds.

Sources for mutation:

Types of mutagens:

Chemical

• Alkylating agents

• Base analogs

• Methylating agents

• DNA intercalating agent

• Reactive oxygen species

UV radiation

Ionizing radiation

Alkylating agents

Alkyl-group on DNA -----> crosslinking G in DNA.

Classical alkylating agentsNitrogen mustards

Cyclophosphamide

Mechlorethamine or mustine

Uracil mustard

Melphalan

Chlorambucil

Ifosfamide

Nitrosoureas

Carmustine, Lomustine and streptozocin

Alkyl sulfonates = Busulfan

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.

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.

Some of DNA intercalating agents

• Berberine

• Ethidiun bromide

• Proflavine

• Daunomycin

• Doxorubicin

• Thalidomide

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)

Radiation

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

• 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

Ionizing Radiation: UV

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

Some unusual mutations

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.

Uner Tan Syndrome

Most obvious property is that people who suffer from it walk on all fours.

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.

Epidermodysplasia Verruciformis

Genetic disorder which makes people very prone to human papilloma virus. Wart like lesion appear all over body.

Severe Combined Immunodeficiency Disorder

Gene 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.

It is the first genetic disease treated by gene therapy

Lesch–Nyhan SyndromeAffects 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.

Ectrodactyly

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

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