Metabolism Biotransformation

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Metabolism - Biotransformation
Supplementary readings Casarett and
Doull,Chapter 6 Timbrell, Chapters 4 and 5
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Non-polar (lipophilic)
Hydrophobic
XENOBIOTIC
Phase I Metabolism
Oxidation
Can accumulate in tissues
Solubility in lipids
INTERMEDIATE METABOLITE
Phase II Metabolism
Conjugation
Solubility in water
May be reactive/toxic
WATER-SOLUBLE METABOLITE
Lipophobic
Hydrophilic (Polar)
ELIMINATION
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What is a xenobiotic ?
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Phase I reactions

• Chemical modification of xenobiotics
• Introduces or uncovers polar functional groups
  that provide sites for Phase II metabolism
• Major classes of reaction
• Oxidation
• Reduction
• Hydrolysis

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Overview of oxidations, reductions, hydrolyses

• Oxidation
• Loss of electrons M M e-
• Gain of oxygen R O RO

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Oxidation reactions
Hydroxylation
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Epoxidation
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Overview of oxidations, reductions, hydrolyses

• Reduction
• Gain of electrons M e- M
• Loss of oxygen RO R O
• Gain of hydrogen R H RH

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Reduction

• Nitro to amino group
• Chromium VI to Chromium III

Cr6 3 e- Cr3
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Hydrolysis

• Addition of water
• Cleavage of R-O or R-N bond accompanied by
  addition of H2O
• R-O-R H2O R-O-H R-OH
• R-N-R H2O R-N-H R-OH
• H H

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Principal Phase I enzymes

• Cytochrome P450
• Flavin monooxygenase
• Monoamine oxidase
• Esterases
• Amidases
• Hydrolases
• Reductases, dehydrogenases, oxidases

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Flavin monooxygenase

• Flavoprotein
• Mixed-function amine oxidase
• Located in smooth endoplasmic reticulum, in
  human, pig, rabbit liver, guinea-pig lung, human
  kidney
• Uses NADPH as a source of reducing equivalents
• Not inducible

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Overall reaction
R-H O2 NADPH H R-OH H2O NADP
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Monoamine oxidase

• Metabolizes endogenous monoamine
  neurotransmitters
• Uses NADPH as a source of reducing equivalents
• Found in the endoplasmic reticulum and in
  mitochondria, of nerve endings and liver

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Esterases

• Hydrolyse esters to carboxylic acid and alcohol
  functional groups
• Non-specific esterases in plasma, more
  substrate-specific forms in liver cytosol

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Amidases

• Hydrolyse amides to carboxylic acids and amines
  (or ammonia)
• Found in plasma and in liver cytosol

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Hydrolases

• Hydrolyse ethers

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Reductases, dehydrogenases, oxidases

• In cytosol, endoplasmic reticulum, mitochondria

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Cytochrome P450

• Heme protein
• Terminal oxidase of the mixed-function oxidase
  (MFO) electron-transfer system
• Located in the smooth endoplasmic reticulum of
  all major organs and tissues
• Uses NADPH as a source of reducing equivalents
• Inducible