Download Biotransformation of xenobiotics and endogenous toxins in the liver

Biotransformation of
xenobiotics and
endogenous toxins in the
liver: microsomal
oxidation, cytochrome Р450.
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
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.
General ways of xenobiotics biotransformation and their localization in cell
REACTION
ENZYME
LOCALIZATION
PHASE I
Hydrolysis
Reduction
Oxidation
Esterase
Peptidase
Epoxide hydrolase
Microsomes, cytosol, lysosomes, blood
lysosomes
Microsomes, cytosol
Azo- and nitro-reduction
Carbonyl reduction
Disulfide reduction
Sulfoxide reduction
Microflora, microsomes, cytosol
Cytosol, blood, microsomes
Cytosol
Cytosol
Alcohol dehydrogenase
Aldehyde dehydrogenase
Aldehyde oxidase
Xanthine oxidase
Monoamine oxidase
Diamine oxidase
Flavin-monooxygenases
Cytochrome P450
Cytosol
Mitochondria, cytosol
Cytosol
Cytosol
Mitochondria
Cytosol
Microsomes
Microsomes
PHASE II
Glucuronide conjugation
Sulfate conjugation
Glutathione conjugation
Amino acid conjugation
Acetylation
Methylation
Microsomes
Cytosol, microsomes
Cytosol
Mitochondria, cytosol
Mitochondria, microsomes
Cytosol, microsomes, blood
PHASE I
Hydrolysis
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.
Oxidation
Alcohol dehydrogenase
Aldehyde dehydrogenase
Oxidizes aldehydes to carbonic acids
Xanthine dehydrogenase-Xanthine oxidase
Monoaminooxidase
Oxidative deamination of amines (serotonin) and
many xenobiotics
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.
SCHEME OF MONOOXYGENASE
SYSTEM
The example of reaction that is catalyzed by cytochrome P450: hydroxylation of
aliphatic carbon
The example of reaction that is catalyzed by cytochrome P450: hydroxylation of
aromatic carbon