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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. Major Phase II reactions. Glucuronidation Sulfation

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phase ii conjugation
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
major phase ii reactions
Major Phase II reactions
  • Glucuronidation
  • Sulfation
  • Conjugation with amino acids
  • Conjugation with glutathione
  • Methylation
  • Acetylation
glucuronidation
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)
reaction
Reaction

Phenol

Phenyl glucuronide

glucuronidation1
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
glucuronidation typical substrates
GlucuronidationTypical substrates:
  • Phenol
  • 1-Naphthol
  • 4-Hydroxybiphenyl
  • 3-Hydroxybenzo[a]pyrene
  • Benzo[a]pyrene-7,8-dihydrodiol
  • 2-Naphthylamine
  • Bilirubin
  • Steroids
sulfation
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
sulfation typical substrates
SulfationTypical substrates
  • Ethanol
  • Phenol
  • 3-Hydroxybenzo[a]pyrene
  • Cholesterol
  • 2-Naphthylamine
  • N-hydroxy-2-naphthylamine
reaction1
Reaction

PAPS

PAP

conjugation with amino acids
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
reaction2
Reaction

Benzoyl-CoA

Hippuric acid

Benzoic acid

conjugation with glutathione
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)
glutathione
Glutathione

A tripeptide

Glutamic acid (Glu)

Glycine (Gly)

Cysteine (Cys)

typical substrates
Typical substrates
  • Organic halides, e.g methyl iodide, benzyl chloride
  • Alkenes e.g. diethyl maleate
  • Epoxides
methylation
Methylation
  • Methyltransferases
  • Target: Hydroxyl groups, amines, thiols
  • Substrates mainly endogenous: Catechols, noradrenalin, histamine
  • Conjugating moiety: Methyl group
  • Co-factor: S-adenosylmethionine
methylation reaction
MethylationReaction

Substrate:

Catechol

Enzyme:

Catechol-O-methyltransferase (COMT)

acetylation
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”
acetylation reaction
AcetylationReaction

2-Naphthylamine

2-Aminonaphthalene

2-Acetylaminonaphthalene

2-Acetamidonaphthalene

other detoxication mechanisms
“Other” detoxication mechanisms
  • P-glycoprotein: ATP-dependent carrier that removes molecules from cells
  • Multidrug resistance associated protein MDR
  • Multispecific organic anion transporter MOAT
reactive oxygen species ros
Reactive Oxygen Species (ROS)
  • Peroxides
    • Hydrogen peroxide HOOH
    • Peroxynitrite OONO-
    • Lipid hydroperoxide LOOH
  • Free radicals
    • Superoxide anion O2•-
    • Hydroxyl radical HO•
    • Nitric oxide NO•
non enzymic reaction with anti oxidants
Non-enzymic reaction with anti-oxidants
  • Ascorbic acid (Vitamin C)
  • alpha-Tocopherol (Vitamin E)
  • Glutathione
superoxide dismutase
Superoxide dismutase

Converts superoxide anions to hydrogen peroxide

O2•- +O2•- + 2H+ O2 + H2O2

peroxidases
Peroxidases

Couple reduction of hydrogen peroxide (or other peroxide) to oxidation of another substrate

(co-oxidation)

ROOH + R’H ROH + R’OH

peroxidases1
Peroxidases
  • Catalase
  • Prostaglandin synthetase
  • Myeloperoxidase
  • Lactoperoxidase
  • Glutathione peroxidase
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