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Metabolism of porphyrins: metabolism of bile pigments, biochemistry of jaundices. 1.

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Presentation on theme: "Metabolism of porphyrins: metabolism of bile pigments, biochemistry of jaundices. 1."— Presentation transcript:

1 Metabolism of porphyrins: metabolism of bile pigments, biochemistry of jaundices.
1

2 JAUNDICES 2

3 NORMAL METABOLISM OF BILE PIGMENTS
CELLS OF RES Indirect bilirubin NADP+ NADPH2 Biliverdin reductase Biliverdin Iron Globin Verdoglobin Hemoxi-genase Hemoglobin ERYTHROCYTES KIDNEYS Stercobilinogen URINE Stercobilin Indirect bilirubin 1,7-20,5 mkmol/l albumin UDP-glucoronil-transferase Direct bilirubin mkmol/l BLOOD LIVER Bilirubin mono-glucoronid, 20 % Bilirubin di-glucoronid, 80 % Dipyrols -glucoro-nidase Glucoronic acid Direct bilirubin BILE INTESTINE Mesobilirubin Mesobilirubin (urobilinogen) STOOL 3

4 METABOLISM OF BILE PIGMENTS IN HEMOLYTIC JAUNDICE
CELLS OF RES Indirect bilirubin albumin Biliverdin reductase UDP-glucoronil-transferase Direct bilirubin NADP+ NADPH2 Biliverdin Iron Globin Verdoglobin Hemoglobin Hemoxi- genase BLOOD LIVER Bilirubin mono-glucoronid, 20 % Bilirubin diglucoronid, 80 % -glucoro- nidase Glucoronic acid BILE ERYTHROCYTES KIDNEYS INTESTINE STOOL Stool hypercholic URINE Urine dark Mesobilirubin Mesobilinogen (urobilinogen) Stercobilinogen Stercobilin Urobilin 4

5 METABOLISM OF BILE PIGMENTS IN HEPATIC JAUNDICE
CELLS OF RES Indirect bilirubin albumin Biliverdin reductase UDP-glucoronil-transferase Direct bilirubin NADP+ NADPH2 Biliverdin Iron Globin Verdoglobin Hemoglobin Hemoxi- genase BLOOD LIVER Bilirubin mono-glucoronid, 20 % Bilirubin diglucoronid, 80 % -glucoro- nidase Glucoronic acid BILE ERYTHROCYTES KIDNEYS Urobilinogen INTESTINE STOOL Stool hypocholic URINE Urine dark Stercobi-linogen Stercobilin Bilirubin Urobilin Mesobilirubin Mesobilinogen (urobilinogen) Stercobilinogen 5

6 METABOLISM OF BILE PIGMENTS IN OBSTRUCTIVE JAUNDICE
CELLS OF RES Indirect bilirubin albumin Biliverdin reductase UDP-glucoronil-transferase Direct bilirubin NADP+ NADPH2 Biliverdin Iron Globin Verdoglobin Hemoglobin Hemoxi- genase BLOOD LIVER Bilirubin mono-glucoronid, 20 % Bilirubin diglucoronid, 80 % Bile acids -glucoro- nidase Glucoronic acid BILE ERYTHROCYTES KIDNEYS INTESTINE STOOL Stool acholic, steatorhea URINE Direct bilirubin Bile acids Urine dark, foaming 6

7 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

8 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

9 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.

10 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

11 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.

12 Alcohol dehydrogenase
Oxidation Alcohol dehydrogenase

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

14 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.

15 SCHEME OF MONOOXYGENASE SYSTEM

16 SCHEME OF MONOOXYGENASE SYSTEM IN ENDOPLASMIC RETICULUM

17

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

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

20 Examples of reactions catalyzed by cytochrome P450: heteroatom oxygenation

21 Examples of reactions catalyzed by cytochrome P450: oxidative group transfer

22 JAUNDICES

23 NORMAL METABOLISM OF BILE PIGMENTS
CELLS OF RES Indirect bilirubin NADP+ NADPH2 Biliverdin reductase Biliverdin Iron Globin Verdoglobin Hemoxi-genase Hemoglobin ERYTHROCYTES KIDNEYS Stercobilinogen URINE Stercobilin Indirect bilirubin 1,7-20,5 mkmol/l albumin UDP-glucoronil-transferase Direct bilirubin mkmol/l BLOOD LIVER Bilirubin mono-glucoronid, 20 % Bilirubin di-glucoronid, 80 % Dipyrols -glucoro-nidase Glucoronic acid Direct bilirubin BILE INTESTINE Mesobilirubin Mesobilirubin (urobilinogen) STOOL

24 Bilirubin di-glucoronid

25 HEMOLYTIC (PREHEPATIC) JAUNDICE
Jaundice due to the excessive breakdown of red blood cells. Causes: sickle cell anemia, malaria, thalassemia, autoimmune disorders, massive hemorrhage

26 METABOLISM OF BILE PIGMENTS IN HEMOLYTIC JAUNDICE
CELLS OF RES Indirect bilirubin albumin Biliverdin reductase UDP-glucoronil-transferase Direct bilirubin NADP+ NADPH2 Biliverdin Iron Globin Verdoglobin Hemoglobin Hemoxi- genase BLOOD LIVER Bilirubin mono-glucoronid, 20 % Bilirubin diglucoronid, 80 % -glucoro- nidase Glucoronic acid BILE ERYTHROCYTES KIDNEYS INTESTINE STOOL Stool hypercholic URINE Urine dark Mesobilirubin Mesobilinogen (urobilinogen) Stercobilinogen Stercobilin Urobilin

27 PARENCHYMAL (HEPATIC) JAUNDICE
occurs due to the liver disease and inability of liver to metabolize and remove bilirubin from the biliary system Causes: cirrhosis, cancer, viral hepatitis, Gilbert’s syndrome, toxins or drugs, etc.

28 METABOLISM OF BILE PIGMENTS IN HEPATIC JAUNDICE
CELLS OF RES Indirect bilirubin albumin Biliverdin reductase UDP-glucoronil-transferase Direct bilirubin NADP+ NADPH2 Biliverdin Iron Globin Verdoglobin Hemoglobin Hemoxi- genase BLOOD LIVER Bilirubin mono-glucoronid, 20 % Bilirubin diglucoronid, 80 % -glucoro- nidase Glucoronic acid BILE ERYTHROCYTES KIDNEYS Urobilinogen INTESTINE STOOL Stool hypocholic URINE Urine dark Stercobi-linogen Stercobilin Bilirubin Urobilin Mesobilirubin Mesobilinogen (urobilinogen) Stercobilinogen

29 ОBSTRUCTIVE (POST-HEPATIC)
JAUNDICE is caused by obstruction of bile flow from the liver Causes: carcinoma in the bile duct or gall bladder, presence of gallstones in the biliary system, infection by parasites, pancreatitis, etc.

30 METABOLISM OF BILE PIGMENTS IN OBSTRUCTIVE JAUNDICE
CELLS OF RES Indirect bilirubin albumin Biliverdin reductase UDP-glucoronil-transferase Direct bilirubin NADP+ NADPH2 Biliverdin Iron Globin Verdoglobin Hemoglobin Hemoxi- genase BLOOD LIVER Bilirubin mono-glucoronid, 20 % Bilirubin diglucoronid, 80 % Bile acids -glucoro- nidase Glucoronic acid BILE ERYTHROCYTES KIDNEYS INTESTINE STOOL Stool acholic, steatorhea URINE Direct bilirubin Bile acids Urine dark, foaming

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