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DETOXIFICATION OF TOXIC SUBSTANCES IN LIVER

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 .

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DETOXIFICATION OF TOXIC SUBSTANCES IN LIVER

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

  2. DETOXIFICATION OF TOXIC SUBSTANCES IN LIVER • Phase Iand 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

  3. 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.

  4. General ways of xenobiotics biotransformation and their localization in cell

  5. 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.

  6. Oxidation Alcohol dehydrogenase

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

  8. Cytochrom P450 The highest concentration – inendoplasmic 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.

  9. SCHEME OF MONOOXYGENASE SYSTEM

  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

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