Biotransformation of Toxicants

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Biotransformation of Toxicants

• Lect 6

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Metabolism (Biotransformation)

• Many xenobiotics undergo chemical transformation
  (biotransformation metabolism)

• Biotransformation is often mediated by enzymes

• Alteration of the parent molecule, or conjugation
  of the parent molecule (or its metabolites) with
  endogenous substances

• Example Cholinesterase metabolize the local
  anesthetic agent procaine and the
  muscle-paralyzing agent succinylcholine.

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Types of Biotransformation Reactions

• Nonsynthetic (Phase I) and synthetic (Phase II)

• Phase I reactions

• Modification of the basic structure of the
  substrate

• No covalent binding of the substrate to an
  endogenous compound

• Examples include hydrolysis, oxidation, and
  reduction reactions

• Phase I enzymes are often membrane-bound (e.g.,
  microsomal).

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Oxidation

• Uses molecular oxygen (O2) one O with H, 2nd O
  with substrate

• Involves several enzymatic steps

• The oxidative system is often known as the mixed
  function oxidase system.

• One subfamily of the mixed function oxidase
  system is the group of enzymes known as
  Cytochrome P-450 enzymes.

• Cytochrome P-450 is a heme-containing cytochrome
  protein located in ER

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Examples of Oxidation Reactions

• Deamination replacement of an amine group (NH2)
  with an oxygen (O) atom

• N-, O-, or S-Dealkylation replacement of an
  alkyl group (e.g., CH3) with a hydrogen atom.
  Typically, the alkyl group in the parent molecule
  is bonded to a N, O, or S atom.

• Aliphatic or aromatic hydroxylation addition of
  a hydroxyl group (OH) to a molecule

• N-oxidation replacement of a hydrogen atom on
  an amine with an oxygen

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Continue

• S-oxidation addition of an oxygen atom to a
  sulfur atom

• Conversion of a hydroxyl group (alcohol) to a
  carboxyl group (acid)

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Reduction

• Azo reduction reduction of an azo bond (NN) to
  two amines (NH2)

• Nitro reduction reduction of a nitro group
  (NO2) to an amine

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Hydrolysis

• Addition of water (H2O) to an ester bond
  (CO-O-C)to form an alcohol (C-OH) and a
  carboxylic acid (COOH)

• R-CO-O-C-R H-O-H ROH R-COOH

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Phase II Reactions

• Involve addition of a cofactor to a substrate to
  form a new product.

• Phase II enzymes may be either microsomal or
  cytosolic.

• Various factors can affect the availability of
  cofactors. For example, fasting markedly reduces
  the amount of glutathione available in the liver.

• Sulfation,Glucuronidation, Acetylation,
  Methylation, Glutathione conjugation, Amino acid
  conjugation and Mercapturic acid formation are
  examples of Phase II Reactions.

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Sulfation

• Replacement of a hydrogen atom (H) with a sulfate
  (SO3)

• Uses the enzyme sulfotransferase

• Uses the cofactor called PAPS (phosphoadenosine
  phosphosulfate)

• Produces a highly water-soluble sulfuric acid
  ester

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Glucuronidation

• Replacement of a hydrogen atom with a glucuronic
  acid

• Uses the enzyme UDP-glucuronosyl transferase
  (UDP-GT)

• Uses the cofactor called UDPGA (uridine
  diphosphate glucuronic acid)

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Acetylation

• Replacement of a hydrogen atom with an acetyl
  group

• Uses the enzyme acetyltransferase

• Uses the cofactor called acetylCoA (acetyl
  coenzyme A)

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Methylation

• Replacement of a hydrogen atom with a methyl group

• Uses the enzyme methyltransferase

• Uses the cofactor called SAM (S-adenosyl
  methionine)

• Common but relatively minor pathway

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Glutathione Conjugation

• Adds a glutathione molecule to the parent
  compound, either by direct addition or by
  replacement of an electrophilic substituent
  (e.g., a halogen atom)

• Uses the enzyme glutathione transferase (GST)

• Uses the cofactor called glutathione (a
  tripeptide madeup of glycine, cysteine, and
  glutamic acid)

• One of the major Phase II enzymatic pathways

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• Amino acid conjugation Adds an amino acid to the
  parent compound.

• Mercapturic acid formation Formed by cleavage of
  the glycine and glutamic acid substituents from a
  glutathione conjugate, followed by N-acetylation
  of the resulting product

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Significance of Biotransformation

• Major part of the pathway for elimination of many
  xenobiotics

• Decrease or an increase (or no change) in toxicity

• Formation of reactive metabolites.

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Metabolism of Acetaminophen
Acetaminophen
Phase I
Phase II
Liver
Liver
Toxic Quinoneimine
Sulfation
Glucuronidation
Covalent Binding
Non Toxic Conjugates
Macromolecules
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Activity of Drug Metabolizing Enzymes