Metabolism of Metabolism of porphyrins: porphyrins:

metabolism of bile metabolism of bile pigments, pigments,

biochemistry of biochemistry of jaundicesjaundices..

JAUNDICES

NORMAL METABOLISM OF BILE PIGMENTS

CELLS OF RESIndirect bilirubin

NADP+

NADPH2

Biliverdin reductase

Biliverdin

Iron

Globin

Verdoglobin

NADP+

Hemoxi-genase

NADPH2

Hemoglobin ERYTHROCYTES

KIDNEYS

Stercobilinogen

URINE

Stercobilin

Indirect bilirubin 1,7-20,5 mkmol/l

albumin

albumin

Indirect bilirubin

UDP-glucoronil-transferase

Direct bilirubin 0.8-4.3 mkmol/l

BLOOD

LIVER

Bilirubin mono-glucoronid, 20 %

Bilirubin di-glucoronid, 80 %

Dipyrols

-glucoro-nidase

Glucoronic acid

Direct bilirubin

BILE

INTESTINE

Mesobilirubin

Mesobilirubin (urobilinogen)

Stercobilinogen

Stercobilin

STOOL

METABOLISM OF BILE PIGMENTS IN HEMOLYTIC JAUNDICE

CELLS OF RES

Indirect bilirubin

Indirect bilirubin

albumin

albumin

Indirect bilirubin

Biliverdin reductase

UDP-glucoronil-transferase

Direct bilirubin

NADP+

NADPH2

Biliverdin

Iron

Globin

Verdoglobin

NADP+

NADPH2

Hemoglobin

Hemoxi- genase

BLOOD

LIVER

Bilirubin mono-glucoronid, 20 %

Bilirubin diglucoronid, 80 %

-glucoro- nidase

Glucoronic acid

Direct bilirubin

BILE

ERYTHROCYTES

KIDNEYS

INTESTINE

STOOL

Stool hypercholic

URINEUrine dark

Mesobilirubin

Mesobilinogen (urobilinogen)

Stercobilinogen

Stercobilin

Stercobilinogen

StercobilinUrobilin

METABOLISM OF BILE PIGMENTS IN HEPATIC JAUNDICE

CELLS OF RES

Indirect bilirubin

Indirect bilirubin

albumin

albumin

Indirect bilirubin

Biliverdin reductase

UDP-glucoronil-transferase

Direct bilirubin

NADP+

NADPH2

Biliverdin

Iron

Globin

Verdoglobin

NADP+

NADPH2

Hemoglobin

Hemoxi- genase

BLOOD

LIVER

Bilirubin mono-glucoronid, 20 %

Bilirubin diglucoronid, 80 %

-glucoro- nidase

Glucoronic acid

Direct bilirubin

BILE

ERYTHROCYTES

KIDNEYS

Urobilinogen INTESTINE

STOOL

Stool hypocholic

URINEUrine dark

Stercobi-linogen

StercobilinBilirubinUrobilin

Mesobilirubin

Mesobilinogen (urobilinogen)

Stercobilinogen

Stercobilin

METABOLISM OF BILE PIGMENTS IN OBSTRUCTIVE JAUNDICE

CELLS OF RESIndirect bilirubin

Indirect bilirubin

albumin

albumin

Indirect bilirubin

Biliverdin reductase

UDP-glucoronil-transferase

Direct bilirubin

NADP+

NADPH2

Biliverdin

Iron

Globin

Verdoglobin

NADP+

NADPH2

Hemoglobin

Hemoxi- genase

BLOOD

LIVER

Bilirubin mono-glucoronid, 20 %

Bilirubin diglucoronid, 80 %

Bile acids

-glucoro- nidase

Glucoronic acid

Direct bilirubin

BILE

Direct bilirubin

ERYTHROCYTES

KIDNEYS

Direct bilirubinINTESTINE

STOOL

Stool acholic, steatorhea

URINE Direct bilirubin Bile acids

Urine dark, foaming

• 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

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.

Cytochrom P450

The highest concentration – in endoplasmic reticulum of hepatocytes (microsomes).

SCHEME OF MONOOXYGENASE SYSTEM

SCHEME OF MONOOXYGENASE SYSTEM IN ENDOPLASMIC RETICULUM

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

Examples of reactions catalyzed by cytochrome P450: heteroatom oxygenation

Examples of reactions catalyzed by cytochrome P450: oxidative group transfer

JAUNDICES

NORMAL METABOLISM OF BILE PIGMENTS

CELLS OF RESIndirect bilirubin

NADP+

NADPH2

Biliverdin reductase

Biliverdin

Iron

Globin

Verdoglobin

NADP+

Hemoxi-genase

NADPH2

Hemoglobin ERYTHROCYTES

KIDNEYS

Stercobilinogen

URINE

Stercobilin

Indirect bilirubin 1,7-20,5 mkmol/l

albumin

albumin

Indirect bilirubin

UDP-glucoronil-transferase

Direct bilirubin 0.8-4.3 mkmol/l

BLOOD

LIVER

Bilirubin mono-glucoronid, 20 %

Bilirubin di-glucoronid, 80 %

Dipyrols

-glucoro-nidase

Glucoronic acid

Direct bilirubin

BILE

INTESTINE

Mesobilirubin

Mesobilirubin (urobilinogen)

Stercobilinogen

Stercobilin

STOOL

Bilirubin di-glucoronid

HEMOLYTIC (PREHEPATIC) JAUNDICE

Jaundice due to the excessive breakdown of red blood cells.

Causes: •sickle cell anemia, •malaria, •thalassemia, •autoimmune disorders,•massive hemorrhage

METABOLISM OF BILE PIGMENTS IN HEMOLYTIC JAUNDICE

CELLS OF RES

Indirect bilirubin

Indirect bilirubin

albumin

albumin

Indirect bilirubin

Biliverdin reductase

UDP-glucoronil-transferase

Direct bilirubin

NADP+

NADPH2

Biliverdin

Iron

Globin

Verdoglobin

NADP+

NADPH2

Hemoglobin

Hemoxi- genase

BLOOD

LIVER

Bilirubin mono-glucoronid, 20 %

Bilirubin diglucoronid, 80 %

-glucoro- nidase

Glucoronic acid

Direct bilirubin

BILE

ERYTHROCYTES

KIDNEYS

INTESTINE

STOOL

Stool hypercholic

URINEUrine dark

Mesobilirubin

Mesobilinogen (urobilinogen)

Stercobilinogen

Stercobilin

Stercobilinogen

StercobilinUrobilin

PARENCHYMAL (HEPATIC) JAUNDICE

occurs due to the liver disease and inability of liver to metabolize and remove bilirubin from the biliary systemCauses:•cirrhosis, •cancer, •viral hepatitis, •Gilbert’s syndrome, toxins or drugs, etc.

METABOLISM OF BILE PIGMENTS IN HEPATIC JAUNDICE

CELLS OF RES

Indirect bilirubin

Indirect bilirubin

albumin

albumin

Indirect bilirubin

Biliverdin reductase

UDP-glucoronil-transferase

Direct bilirubin

NADP+

NADPH2

Biliverdin

Iron

Globin

Verdoglobin

NADP+

NADPH2

Hemoglobin

Hemoxi- genase

BLOOD

LIVER

Bilirubin mono-glucoronid, 20 %

Bilirubin diglucoronid, 80 %

-glucoro- nidase

Glucoronic acid

Direct bilirubin

BILE

ERYTHROCYTES

KIDNEYS

Urobilinogen INTESTINE

STOOL

Stool hypocholic

URINEUrine dark

Stercobi-linogen

StercobilinBilirubinUrobilin

Mesobilirubin

Mesobilinogen (urobilinogen)

Stercobilinogen

Stercobilin

is caused by obstruction of bile flow from the liver

ОBSTRUCTIVE (POST-HEPATIC) JAUNDICE

Causes: •carcinoma in the bile duct or gall bladder, •presence of gallstones in the biliary system, •infection by parasites, •pancreatitis, etc.

METABOLISM OF BILE PIGMENTS IN OBSTRUCTIVE JAUNDICE

CELLS OF RESIndirect bilirubin

Indirect bilirubin

albumin

albumin

Indirect bilirubin

Biliverdin reductase

UDP-glucoronil-transferase

Direct bilirubin

NADP+

NADPH2

Biliverdin

Iron

Globin

Verdoglobin

NADP+

NADPH2

Hemoglobin

Hemoxi- genase

BLOOD

LIVER

Bilirubin mono-glucoronid, 20 %

Bilirubin diglucoronid, 80 %

Bile acids

-glucoro- nidase

Glucoronic acid

Direct bilirubin

BILE

Direct bilirubin

ERYTHROCYTES

KIDNEYS

Direct bilirubinINTESTINE

STOOL

Stool acholic, steatorhea

URINE Direct bilirubin Bile acids

Urine dark, foaming