DETOXIFICATION OF TOXIC SUBSTANCES IN LIVER
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Transcript of DETOXIFICATION OF TOXIC SUBSTANCES IN LIVER
Biotransformation of xenobiotics and
endogenous toxins in the liver: microsomal oxidation, cytochrome
Р-450.
DETOXIFICATION OF TOXIC DETOXIFICATION OF TOXIC SUBSTANCES IN LIVERSUBSTANCES 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.
REACTION ENZYME LOCALIZATION
PHASE I
Hydrolysis
Reduction
Oxidation
EsterasePeptidase Epoxide hydrolase
Azo- and nitro-reduction Carbonyl reductionDisulfide reductionSulfoxide reduction
Alcohol dehydrogenaseAldehyde dehydrogenaseAldehyde oxidaseXanthine oxidaseMonoamine oxidaseDiamine oxidaseFlavin-monooxygenasesCytochrome P450
Microsomes, cytosol, lysosomes, blood lysosomes Microsomes, cytosol
Microflora, microsomes, cytosolCytosol, blood, microsomesCytosolCytosol
CytosolMitochondria, cytosolCytosolCytosolMitochondriaCytosolMicrosomesMicrosomes
PHASE II
Glucuronide conjugationSulfate conjugationGlutathione conjugationAmino acid conjugationAcetylationMethylation
MicrosomesCytosol, microsomesCytosolMitochondria, cytosolMitochondria, microsomesCytosol, microsomes, blood
General ways of xenobiotics biotransformation and their localization in cell
PHASE I
Hydrolysis
Esterases (carboxyesterases, cholinesterases, phosphatases) Peptidases
ReductionMetals and xenobiotics containing aldehyde, keto, disulfide, alkyn, azo, or nitro group are often reduced
Reducing agents:Reduced glutathione, FADH2, FMN,NADH NADPH.
OxidationAlcohol 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