Biochemical functions of liver 1

LIVER STRUCTURE sinusoids central vein portal vein bile canaliculi hepatic artery bile duct sinusoids bile canaliculi central vein 2

LIVER 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 3

METABOLISM OF CARBS IN LIVER 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 4

METABOLISM OF LIPIDS IN LIVER 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 5

METABOLISM OF PROTEINS IN LIVER 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 6

VITAMIN METABOLISM IN LIVER 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 7

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 8

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. 9

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 10

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. 11

Alcohol dehydrogenase Oxidation Alcohol dehydrogenase 12

Aldehyde dehydrogenase Xanthine dehydrogenase-Xanthine oxidase Oxidizes aldehydes to carbonic acids Xanthine dehydrogenase-Xanthine oxidase Monoaminooxidase Oxidative deamination of amines (serotonin) and many xenobiotics 13

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. 14

SCHEME OF MONOOXYGENASE SYSTEM 15

16

The example of reaction that is catalyzed by cytochrome P450: hydroxylation of aliphatic carbon 17

The example of reaction that is catalyzed by cytochrome P450: hydroxylation of aromatic carbon 18