1. Biotransformation of xenobiotics and endogenous toxins in the liver: microsomal oxidation, cytochrome Р-450.

2. DETOXIFICATION OF TOXIC SUBSTANCES IN LIVER
Phase I and phase II.
Phase I:
hydrolysis,
reduction,
oxidation.
These reactions introduce functional group (—OH, —NH2, —SH, or —COOH) and usually result in a little increase of hydrophylic properties 2

3. conjugation with glutathione,
Phase II includes:
glucuronation,
sulfation,
acetylation,
methylation,
conjugation with glutathione,
conjugation with aminoacids (glycin, taurin, glutamic acid)
Phase II results in the marked increase of hydrophylic properties of xenobiotic. 3

4. General ways of xenobiotics biotransformation and their localization in cell
REACTION
ENZYME
LOCALIZATION
PHASE I
Hydrolysis
Reduction
Oxidation
Esterase
Peptidase Epoxide hydrolase
Azo- and nitro-reduction
Carbonyl reduction
Disulfide reduction
Sulfoxide reduction
Alcohol dehydrogenase
Aldehyde dehydrogenase
Aldehyde oxidase
Xanthine oxidase
Monoamine oxidase
Diamine oxidase
Flavin-monooxygenases
Cytochrome P450
Microsomes, cytosol, lysosomes, blood lysosomes Microsomes, cytosol
Microflora, microsomes, cytosol
Cytosol, blood, microsomes
Cytosol
Mitochondria, cytosol
Mitochondria
Microsomes
PHASE II
Glucuronide conjugation
Sulfate conjugation
Glutathione conjugation
Amino acid conjugation
Acetylation
Methylation
Cytosol, microsomes
Mitochondria, microsomes
Cytosol, microsomes, blood 4

5. PHASE I Hydrolysis Reduction
Esterases (carboxyesterases, cholinesterases, phosphatases)
Peptidases
Reduction
Metals and xenobiotics containing aldehyde, keto, disulfide, alkyn, azo, or nitro group are often reduced
Reducing agents:
Reduced glutathione,
FADH2,
FMN,
NADH
NADPH. 5

6. Alcohol dehydrogenase
Oxidation
Alcohol dehydrogenase 6

7. Aldehyde dehydrogenase Xanthine dehydrogenase-Xanthine oxidase
Oxidizes aldehydes to carbonic acids
Xanthine dehydrogenase-Xanthine oxidase
Monoaminooxidase
Oxidative deamination of amines (serotonin) and many xenobiotics 7

8. Cytochrom P450
The highest concentration – in endoplasmic reticulum of hepatocytes (microsomes).
Hem containing protein.
Catalyzes monooxigenation of oxygen atom into substrate; another oxygen atom is reduced to water
Electrons are transferred from NADPH to cytochrome P450 through flavoprotein NADPH-cytochrome P450 reductase. 8

9. SCHEME OF MONOOXYGENASE SYSTEM9

10. 10

11. The example of reaction that is catalyzed by cytochrome P450: hydroxylation of aliphatic carbon11

12. The example of reaction that is catalyzed by cytochrome P450: hydroxylation of aromatic carbon12