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Understanding Phase II Conjugation Reactions: Mechanisms and Importance in Xenobiotic Metabolism

This article explores Phase II conjugation reactions in the metabolism of xenobiotics, focusing on various synthetic reactions that enhance the water solubility and excretion of these compounds. Key reactions discussed include glucuronidation, sulfation, amino acid conjugation, and glutathione conjugation, each elaborated with their respective enzymes, substrate targets, co-factors, and specific examples. Furthermore, detoxification mechanisms involving P-glycoprotein and reactive oxygen species are examined, providing insight into the body's defense against harmful substances.

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Understanding Phase II Conjugation Reactions: Mechanisms and Importance in Xenobiotic Metabolism

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  1. Phase II: Conjugation • Synthetic reaction of a xenobiotic (or of a Phase I metabolite of a xenobiotic) with an endogenous substance • Results in introduction of polar, ionizable groups to enhance water solubility and hence excretion

  2. Major Phase II reactions • Glucuronidation • Sulfation • Conjugation with amino acids • Conjugation with glutathione • Methylation • Acetylation

  3. Glucuronidation • Enzyme: glucuronyl transferase, or glucuronosyl transferase • Targets: • hydroxyl groups: Phenols, Alcohols, Dihydrodiols (ether glucuronides) • Carboxylic acids (ester glucuronides) • Amines (N-glucuronides) • Thiols (S-glucuronides) • Carbon (C-glucuronides, rare)

  4. Reaction Phenol Phenyl glucuronide

  5. Glucuronidation • Conjugating moiety: glucuronic acid, a sugar • Co-factor: UDP-glucuronic acid (UDPGA), derived from glycogen synthesis • Located in endoplasmic reticulum • Multiple families of isoforms:UGT1, UGT2 • UGT1.1 ..1.7, UGT2.1..2.4 • Inducible

  6. Uridine-5’-diphospho--D-glucuronic acid (UDPGA)

  7. GlucuronidationTypical substrates: • Phenol • 1-Naphthol • 4-Hydroxybiphenyl • 3-Hydroxybenzo[a]pyrene • Benzo[a]pyrene-7,8-dihydrodiol • 2-Naphthylamine • Bilirubin • Steroids

  8. Sulfation • Sulfotransferase ST,15 isoforms (xx-ST) • Targets • Hydroxyl groups (phenols, alcohols) • Amino groups • Thiols • Conjugating moiety: sulfuric acid, H2SO4 • Co-factor: 3’phosphoadenosine 5’phosphosulfate (PAPS), formed from ATP + sulfate • Located in cytosol, Probably not inducible

  9. SulfationTypical substrates • Ethanol • Phenol • 3-Hydroxybenzo[a]pyrene • Cholesterol • 2-Naphthylamine • N-hydroxy-2-naphthylamine

  10. Reaction PAPS PAP

  11. Conjugation with amino acids • Amino acid transferases • Targets: carboxylic acids • Conjugating moieties: Glycine, glutamine, alanine, taurine, histidine, ornithine • Co-factor: Acetyl CoA (CoASH) and ATP • In cytosol

  12. Reaction Benzoyl-CoA Hippuric acid Benzoic acid

  13. Conjugation with glutathione • Glutathione S-transferases (GST) • Targets: Epoxides, halogens • Conjugating moiety: Glutathione • Co-factor: None • Mainly in cytosol • Inducible • Multiple families of isoforms: GSTA, GSTM, GSTP, GSTT ()(αμπθ)

  14. Glutathione A tripeptide Glutamic acid (Glu) Glycine (Gly) Cysteine (Cys)

  15. Reaction

  16. Typical substrates • Organic halides, e.g methyl iodide, benzyl chloride • Alkenes e.g. diethyl maleate • Epoxides

  17. Mercapturic acid pathway

  18. Methylation • Methyltransferases • Target: Hydroxyl groups, amines, thiols • Substrates mainly endogenous: Catechols, noradrenalin, histamine • Conjugating moiety: Methyl group • Co-factor: S-adenosylmethionine

  19. S-adenosylmethionine

  20. MethylationReaction Substrate: Catechol Enzyme: Catechol-O-methyltransferase (COMT)

  21. Acetylation • N-acetyltransferases (NAT) • Target: Aromatic amines, sulfonamides • Conjugating moiety: Acetyl group • Co-factor: Acetyl-CoA • Few forms: NAT1, NAT2. NAT3: mice • Genetic polymorphisms: “slow and fast acetylators”

  22. AcetylationReaction 2-Naphthylamine 2-Aminonaphthalene 2-Acetylaminonaphthalene 2-Acetamidonaphthalene

  23. “Other” detoxication mechanisms • P-glycoprotein: ATP-dependent carrier that removes molecules from cells • Multidrug resistance associated protein MDR • Multispecific organic anion transporter MOAT

  24. Reactive Oxygen Species (ROS) • Peroxides • Hydrogen peroxide HOOH • Peroxynitrite OONO- • Lipid hydroperoxide LOOH • Free radicals • Superoxide anion O2•- • Hydroxyl radical HO• • Nitric oxide NO•

  25. Non-enzymic reaction with anti-oxidants • Ascorbic acid (Vitamin C) • alpha-Tocopherol (Vitamin E) • Glutathione

  26. Superoxide dismutase Converts superoxide anions to hydrogen peroxide O2•- +O2•- + 2H+ O2 + H2O2

  27. Peroxidases Couple reduction of hydrogen peroxide (or other peroxide) to oxidation of another substrate (co-oxidation) ROOH + R’H ROH + R’OH

  28. Peroxidases • Catalase • Prostaglandin synthetase • Myeloperoxidase • Lactoperoxidase • Glutathione peroxidase

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