Download Phase I

LIVER
BIOCHEMISTRY
LIVER STRUCTURE
sinusoids
central vein
portal vein
bile canaliculi
bile duct
hepatic artery
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
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
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
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
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
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
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.
General ways of xenobiotics biotransformation and their localization in cell
REACTION
ENZYME
LOCALIZATION
PHASE I
Hydrolysis
Reduction
Oxidation
Esterase
Peptidase
Epoxide hydrolase
Microsomes, cytosol, lysosomes, blood
lysosomes
Microsomes, cytosol
Azo- and nitro-reduction
Carbonyl reduction
Disulfide reduction
Sulfoxide reduction
Microflora, microsomes, cytosol
Cytosol, blood, microsomes
Cytosol
Cytosol
Alcohol dehydrogenase
Aldehyde dehydrogenase
Aldehyde oxidase
Xanthine oxidase
Monoamine oxidase
Diamine oxidase
Flavin-monooxygenases
Cytochrome P450
Cytosol
Mitochondria, cytosol
Cytosol
Cytosol
Mitochondria
Cytosol
Microsomes
Microsomes
PHASE II
Glucuronide conjugation
Sulfate conjugation
Glutathione conjugation
Amino acid conjugation
Acetylation
Methylation
Microsomes
Cytosol, microsomes
Cytosol
Mitochondria, cytosol
Mitochondria, microsomes
Cytosol, microsomes, blood
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.
Oxidation
Alcohol 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 NADPHcytochrome P450 reductase.
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 RES
Indirect
bilirubin 1,720,5 mkmol/l
Indirect
bilirubin
NADP+
Biliverdin
reductase
NADPH2
albumin
Indirect
bilirubin
UDP-glucoroniltransferase
albumin
Bilirubin monoglucoronid, 20 %
Biliverdin
Iron
Globin
Verdoglobin
NADP+
Hemoxigenase
Direct
bilirubin 0.84.3 mkmol/l
B
L
O
O
D
Bilirubin di-glucoronid,
80 %
L
I
V
E
R
Dipyrols
 -glucoronidase
Glucoronic
acid
NADPH2
Hemoglobin
ERYTHROCYTES
B
I
L
E
Direct
bilirubin
K
I
D
N
E
Y
S
Mesobilirubin
Mesobilirubin
(urobilinogen)
Stercobilinogen
Stercobilinogen
I
N
T
E
S
T
I
N
E
STOOL
URINE
Stercobilin
Stercobilin
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
NADP+
Indirect
bilirubin
Biliverdin
reductase
NADPH2
albumin
Indirect
bilirubin
UDP-glucoroniltransferase
albumin
L
I
V
E
R
Bilirubin monoglucoronid, 20 %
Biliverdin
Iron
Direct
bilirubin
Globin
Bilirubin diglucoronid,
80 %
Verdoglobin
NADP+
Hemoxigenase
B
L
O
O
D
 -glucoronidase
Glucoronic
acid
NADPH2
Hemoglobin
ERYTHROCYTES
Direct
bilirubin
K
I
D
N
E
Y
S
Mesobilirubin
Mesobilinogen
(urobilinogen)
Stercobilinogen
Stercobilinogen
Urobilin
B
I
L
E
I
N
T
E
S
T
I
N
E
Stercobilin
STOOL
Stercobilin
URINE
Urine dark
Stool hypercholic
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.
METABOLISM OF BILE PIGMENTS IN HEPATIC
JAUNDICE
CELLS OF RES
albumin
Indirect
bilirubin
Indirect
bilirubin
NADP+
Biliverdin
reductase
NADPH2
Indirect
bilirubin
UDP-glucoroniltransferase
albumin
L
I
V
E
R
Bilirubin monoglucoronid, 20 %
Biliverdin
B
L
O
O
D
Iron
Globin
Verdoglobin
Direct
bilirubin
Bilirubin diglucoronid,
80 %
NADP+
-glucoro-
Hemoxigenase
nidase
Glucoronic
acid
NADPH2
ERYTHROCYTES
Hemoglobin
Direct
bilirubin
K
I
D
N
E
Y
S
Mesobilirubin
Urobilinogen
Mesobilinogen
(urobilinogen)
Stercobilinogen
Stercobilinogen
Urobilin
Bilirubin
B
I
L
E
I
N
T
E
S
T
I
N
E
Stercobilin
STOOL
URINE
Urine dark
Stercobilin
Stool hypocholic
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.
METABOLISM OF BILE PIGMENTS IN OBSTRUCTIVE
JAUNDICE
albumin
CELLS OF RES
Indirect
bilirubin
NADP+
Indirect
bilirubin
Biliverdin
reductase
NADPH2
Indirect
bilirubin
UDP-glucoroniltransferase
albumin
Bilirubin monoglucoronid, 20 %
Biliverdin
Iron
Direct
bilirubin
Globin
Verdoglobin
NADP+
Hemoxigenase
B
L
O
O
D
Bilirubin diglucoronid,
80 %
Bile
acids
 -glucoronidase
Glucoronic
acid
NADPH2
ERYTHROCYTES
Hemoglobin
Direct
bilirubin
K
I
D
N
E
Y
S
URINE
L
I
V
E
R
Direct
B
I
L
E
Direct
bilirubin
I
N
T
E
S
T
I
N
E
bilirubin
Direct bilirubin Bile acids
Urine dark, foaming
STOOL
Stool acholic, steatorhea