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Induction

Induction. Increased transcription Increased protein synthesis Enhanced stability of protein Synthesis of enzyme with higher catalytic activity. Inducible forms of CYP: CYP1A1 (PAH), CYP2B, CYP3A4 (PB), CYP2E1 (EtOH) Constitutive: CYP2A http://medicine.iupui.edu/flockhart/table.htm.

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Induction

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  1. Induction • Increased transcription • Increased protein synthesis • Enhanced stability of protein • Synthesis of enzyme with higher catalytic activity Inducible forms of CYP: CYP1A1 (PAH), CYP2B, CYP3A4 (PB), CYP2E1 (EtOH) Constitutive: CYP2A http://medicine.iupui.edu/flockhart/table.htm

  2. Example: AhR, receptor in cytoplasm, binds ligand: eg PAHs, TCDD, some PCBs Bound AhR loses 2 heat-shock proteins (hsp90), becomes phosphorylated Activated bound AhR migrates to nucleus, forms complex with Ah receptor nuclear translocation factor Arnt AhR-Arnt complex binds to regulatory sequences in DNA (DRE, dioxin-responsive elements) Transcription of CYP1A1 gene and other genes Ah-locus mediated induction

  3. Other “inducers” also interact with receptors • CAR, responds to phenobarbital-type inducers, regulates CYP2B, CYP3A4, CYP reductase, transferases (?) • PXR, CYP3A • PPARα, CYP4A • LXR, FXR control enzymes involved in bile acid and lipid metabolism

  4. 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

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

  6. 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)

  7. Reaction Phenol Phenyl glucuronide

  8. 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

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

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

  11. 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

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

  13. Reaction PAPS PAP

  14. 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

  15. Reaction Benzoyl-CoA Hippuric acid Benzoic acid

  16. 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)

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

  18. Reaction

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

  20. Mercapturic acid pathway

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