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

Metabolism of porphyrins: metabolism of bile pigments, biochemistry of jaundices. JAUNDICES. NORMAL METABOLISM OF BILE PIGMENTS. albumin. CELLS OF RES. Indirect bilirubin 1,7-20,5 mkmol/l. Indirect bilirubin. Indirect bilirubin. UDP-glucoronil-transferase. NADP +.

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

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

  2. JAUNDICES

  3. NORMAL METABOLISM OF BILE PIGMENTS albumin CELLS OF RES Indirect bilirubin 1,7-20,5 mkmol/l Indirect bilirubin Indirect bilirubin UDP-glucoronil-transferase NADP+ Biliverdin reductase albumin NADPH2 LIVER Bilirubin mono-glucoronid, 20 % Biliverdin Direct bilirubin 0.8-4.3 mkmol/l Iron Globin Bilirubin di-glucoronid, 80 % Verdoglobin BLOOD Dipyrols NADP+ Hemoxi-genase -glucoro-nidase Glucoronic acid NADPH2 ERYTHROCYTES BILE Hemoglobin Direct bilirubin KIDNEYS INTESTINE Mesobilirubin Mesobilirubin (urobilinogen) Stercobilinogen Stercobilinogen STOOL URINE Stercobilin Stercobilin

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

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

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

  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 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

  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

  11. 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.

  12. Oxidation Alcohol dehydrogenase

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

  14. 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.

  15. SCHEME OF MONOOXYGENASE SYSTEM

  16. SCHEME OF MONOOXYGENASE SYSTEMIN ENDOPLASMIC RETICULUM

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

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

  19. Examples of reactions catalyzed by cytochrome P450: heteroatom oxygenation

  20. Examples of reactions catalyzed by cytochrome P450: oxidative group transfer

  21. JAUNDICES

  22. NORMAL METABOLISM OF BILE PIGMENTS albumin CELLS OF RES Indirect bilirubin 1,7-20,5 mkmol/l Indirect bilirubin Indirect bilirubin UDP-glucoronil-transferase NADP+ Biliverdin reductase albumin NADPH2 LIVER Bilirubin mono-glucoronid, 20 % Biliverdin Direct bilirubin 0.8-4.3 mkmol/l Iron Globin Bilirubin di-glucoronid, 80 % Verdoglobin BLOOD Dipyrols NADP+ Hemoxi-genase -glucoro-nidase Glucoronic acid NADPH2 ERYTHROCYTES BILE Hemoglobin Direct bilirubin KIDNEYS INTESTINE Mesobilirubin Mesobilirubin (urobilinogen) Stercobilinogen Stercobilinogen STOOL URINE Stercobilin Stercobilin

  23. Bilirubin di-glucoronid

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

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

  26. 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.

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

  28. 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.

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

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