Phase ii conjugation
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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

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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


Uridine 5 diphospho d glucuronic acid udpga

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


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)


Reaction3

Reaction


Typical substrates

Typical substrates

  • Organic halides, e.g methyl iodide, benzyl chloride

  • Alkenes e.g. diethyl maleate

  • Epoxides


Mercapturic acid pathway

Mercapturic acid pathway


Methylation

Methylation

  • Methyltransferases

  • Target: Hydroxyl groups, amines, thiols

  • Substrates mainly endogenous: Catechols, noradrenalin, histamine

  • Conjugating moiety: Methyl group

  • Co-factor: S-adenosylmethionine


S adenosylmethionine

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’HROH + R’OH


Peroxidases1

Peroxidases

  • Catalase

  • Prostaglandin synthetase

  • Myeloperoxidase

  • Lactoperoxidase

  • Glutathione peroxidase


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