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Biotransformation of Toxicants

Biotransformation of Toxicants. Lect 6. Metabolism (Biotransformation). Many xenobiotics undergo chemical transformation (biotransformation; metabolism) . Biotransformation is often mediated by enzymes .

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Biotransformation of Toxicants

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  1. Biotransformation of Toxicants Lect 6

  2. 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.

  3. 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).

  4. 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

  5. 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

  6. Continue • S-oxidation – addition of an oxygen atom to a sulfur atom • Conversion of a hydroxyl group (alcohol) to a carboxyl group (acid)

  7. Reduction • Azo reduction – reduction of an azo bond (N=N) to two amines (NH2) • Nitro reduction – reduction of a nitro group (NO2) to an amine

  8. 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

  9. 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.

  10. 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

  11. 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)

  12. Acetylation • Replacement of a hydrogen atom with an acetyl group • Uses the enzyme acetyltransferase • Uses the cofactor called acetylCoA (acetyl coenzyme A)

  13. 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

  14. 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

  15. 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

  16. 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.

  17. Metabolism of Acetaminophen Acetaminophen Phase I Phase II Liver Liver Toxic Quinoneimine Sulfation Glucuronidation Covalent Binding Non Toxic Conjugates Macromolecules

  18. Activity of Drug Metabolizing Enzymes

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