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

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

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

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

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

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

Alcohol dehydrogenase Oxidation Alcohol dehydrogenase 6

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

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

SCHEME OF MONOOXYGENASE SYSTEM 9

10

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

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