Biochemical functions Biochemical functions of liverof liver

portal vein

hepatic artery

bile duct

sinusoids

bile canaliculi

central vein

LIVER STRUCTURELIVER STRUCTURE

LIVER FUNCTIONSLIVER FUNCTIONS

•Distribution of nutrients•All types of metabolism (protein, lipid, carbohydrate, vitamin, mineral)•Excretory (bile acids, urea synthesis)•Destruction of toxic substances•Depot of iron, vitamins

METABOLISM OF CARBS IN METABOLISM OF CARBS IN LIVERLIVER

glycolisis metabolism of fructose and galactose gluconeogenesis release of glucose into blood (maintain the stable glucose concentration in blood) conversion of pyruvate into acetyl CoA tricarboxylic acid cycle pentose phosphate pathway glycogenolysis, glycogenogenesis

METABOLISM OF LIPIDS IN METABOLISM OF LIPIDS IN LIVERLIVER

synthesis of lipoproteins synthesis of triacylglyserols synthesis of phospholipids synthesis of fatty acids, elongation of fatty acids chain, desaturation synthesis of cholesterol ketone bodies formation lipolysis fatty acids oxidation

METABOLISM OF PROTEINS IN METABOLISM OF PROTEINS IN LIVERLIVER

protein synthesis, including blood plasma proteins protein decomposition; urea synthesis conversion of proteins into carbs and lipids interconversion of aminoacids conversion of proteins into low molecular weight nitrogen containing substances

• Formation of active form of vitamin D

• Formation of vitamin A from carotins

• Depo of cyanocobalamine and folic acid

• Depo of vitamin E• Phosphorilation of vitamins B,

formation of coenzyme forms

VITAMIN METABOLISM IN LIVER

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