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