Mechanisms of Toxic Action

1
Mechanisms of Toxic Action

• How Chemical Compounds Affect Cells in a Toxic
  Manner

2
Toxic Action At Specific Locations

• Due to
• Specialized membrane transport processes active
  transport into cells
• Generation of Electrophiles
• Generation of Free Radicals
• Lipid Peroxidation

3
Toxic Action Due to Specific Uptake Mechanisms

• Example used is MPTP
• 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• See handout and overhead for specific information.

4
Activated Chemical Compounds

• Electrophiles are molecules that contain an
  electron deficient atom with partial or full
  positive charge.
• Examples of organic compound electrophiles are
  carbonium and nitrenium ions epoxides are
  another example of an organic electrophile
• The conversion of Hg0 to Hg1 and Hg2 are
  examples of inorganic electrophiles

5
Electrophiles (Continued)

• Electrophiles react with nucleophilic centers in
  proteins and nucleic acids to form adducts
• Go through example of benzoapyrene metabolism
  and adduct formation bring handout showing
  benzoapyrene metabolism
• Adduct formation can lead to point mutations in
  DNA, example will be given.

6
Adduct Formation

• Expoxide metabolites of benzoapyrene and
  Aflatoxin B1 bind to N7 of guanine nucleotide
  bases.
• The guanine nucleotide base will now pair with an
  adenine base during DNA replication, not with its
  normal cytosine base pair.
• See notes on blackboard for how point mutation
  takes place
• See overhead handout for how this mutation can
  lead to the development of cancer

7
Free Radicals

• A Free Radical is a molecule or molecular
  fragment that contains one or more unpaired
  electrons in its out orbital.
• Free Radicals can be formed by
• Accepting or losing an electron
• Homolytic fission of a covalent bond

8
Formation of Free Radicals (Continued)

• Example of a compound that becomes a Free Radical
  by accepting or losing an electron
• Paraquat a herbicide that was used on marijuana
  crops to kill plants
• Inside the body Paraquat is taken up by active
  transport into Type I and Type II cells in the
  alveoli
• Paraquat undergoes Redox Cycling within cells,
  kills cells see handout for example

9
Formation of Free Radicals (Continued)

• Formation of a Free Radical by homolytic bond
  fission
• Example is CCl4 Carbon Tetrachloride
• Chemical reaction diagram will be given on
  overhead

10
Formation of Free Radicals (Continued)

• Homolytic bond fission of HOOH (hydrogen
  peroxide), The pulmonary toxicity of mineral
  particles such as asbestos and silica is caused,
  at least in part, by the formation of the OH
  radical through a reaction termed the Fenton
  Reaction.
• See overhead for example

11
Detoxification of Free Radicals

• The involvement of (1) supraoxide dismutase, (2)
  glutathione, (3) glutathione peroxidase, and (4)
  catalase
• We will go over an example on the overhead
  showing how these compounds are involved in
  removing Free Radicals from the system so that no
  toxic action occurs.

12
Damage From Free Radicals

• Covalent binding of the Free Radical to lipid and
  protein molecules
• Lipid Peroxidation
• We will go over a specific example to show how
  lipid peroxidation takes place.