seminar no. 6 - chapter 15 (partly) -
DESCRIPTION
Metabolic functions of liver (not in seminar book) Catabolism of hem (Chapter 15) Biotransformations of xenobiotics (not in seminar book). Seminar No. 6 - Chapter 15 (partly) -. Glucose metabolism in liver. well-fed state (insulin): glycogenesis, glycolysis - PowerPoint PPT PresentationTRANSCRIPT
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Metabolic functions of liver (not in seminar book)
Catabolism of hem (Chapter 15)
Biotransformations of xenobiotics (not in seminar book)
Seminar No. 6
- Chapter 15 (partly) -
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Glucose metabolism in liver
• well-fed state (insulin): glycogenesis, glycolysis
• fasting (glucagon): glycogenolysis, gluconeogenesis
• other pathways:
pentose cycle (ribose, other pentoses, NADPH)
the isomeration of glucose to galactose
the conversion of fructose and galactose to glucose
synth. of derivatives: glucuronic acid,
glucosamine .....
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Aminoacid metabolism in liver
• synthesis of most plasma proteins
• up-take and degradation of plasma proteins + peptide hormons
• catabolism of AA
(transamination - ALT, deamination - GMD)
• synthesis of non-essential AA
• detoxication of ammonia (urea, glutamine)
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Lipid metabolism in liver
• synthesis of FA and TAG
• synthesis of phospholipids
• synthesis of lipoproteins (VLDL, HDL)
• degradation of TAG/PL - CM remnants, IDL, LDL, HDL2
(hepatic lipase, lysosome)
• β-oxidation of FA
• synthesis of KB – for export only
succinyl-CoA:acetoacetate-CoA transferase (for
activation of acetoacetate) is not in liver
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Cholesterol metabolism in liver
• synthesis of cholesterol
• excretion of cholesterol into bile
• synthesis of bile acids
• conjugation of bile acids
• excretion of bile acids into bile
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The localization of metabolic processes(see also p. 56)
Periportal hepatocytes Perivenous hepatocytes
β-oxidation of FA
CAC
gluconeogenesis
glycogen synthesis
transamination of AA
urea synthesis
cholesterol synthesis
ROS elimination
glycolysis
FA/TAG synthesis
Gln synthesis (NH3 detox.)
Biotransformation reactions:
hydroxylations (cyt P-450)
conjugations
ethanol dehydrogenation
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Catabolism of hem
p. 88
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Hem is a chelate of protoporphyrin IX with Fe2+
protoporfyrin IX
Fe
hem
HN N
NNCH3H3C
CH3
H3C
COOHHOOC
H
askorbát
Fe3+
- 2H+N N
NNCH3H3C
CH3
H3C
COOHHOOC
Fe2+
ascorbic acid
AB
C D
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Catabolism of hem
• occurs mainly in spleen, liver, bone marrow
• hemoxygenase (O2, NADPH, cytochrome P-450)
• Fe2+ is released and oxidized to Fe3+, bound to ferritin (store)
• -CH= between A/B rings is split off as carbon monoxide (CO)
• two O atoms are attached to the A+B pyrrole rings biliverdin
• the central -C= bridge between C/D rings in biliverdin is then
reduced to -CH2- bridge bilirubin
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Hem degradation provides CO and bilirubin
N HN
NNH
oxidative splitting
CO + biliverdin + 3 H2O
bilirubin
3 O2 + 3 NADPH+H+
AB
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Three oxygen atoms attack protoporphyrin
N HN
NNH
AB
OOO
one O is incorporated into CO, two O atoms are inserted into bilirubin
hemoxygenase
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Q.
What happens with CO in human body?
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Carbonylhemoglobin (CO-Hb) in blood
Subject / Situation CO-Hb (%)*
Newborns
Adults (rural areas)
Adults (big cities)
Smokers
Traffic policemen
Poisoning
Death
0.4
1-2
4-5
10-12
12-15
20-50
55-60
Endogenous CO
Exogenous CO
* Percentage of total hemoglobin
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Text-book structure of bilirubin
N
CH2 CH3
CH2
COOH
N
CH3
O
CH2
NO
H2C
H3C
N
CH3 CH2
CH2
CHOO
H H H H
bilirubinbilirubin has eight polar groups:
2 -COOH 2 C=O 4 -NH-
despite it bilirubine is non-polar compound
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Q.
Why is bilirubin non-polar compound?
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Properties of bilirubin
• linear tetrapyrrol system
• free rotation around central -CH2- is possible
• non-linear conformation arises, stabilized by six
intramolecular H-bonds
• all polar groups are involved in H-bonds
• consequence: free bilirubin is non-polar, insoluble in
water, in plasma – bound to albumin
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Real structure of bilirubin
with six intramolecular H-bonds
NO NH
H
C
O
OH
NNC
O
OH
HH O
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Q.
What is UDP-GlcA?
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Uridine diphoshoglucuronic acid
N
OHOH
O
NH
O
O
OP
O
O
O
PO
O
OO
OH
O
COO
HH
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Conjugation of bilirubin in liver
• bilirubin reacts with two molecules of UDP-glucuronate
• two highly polar molecules of glucuronate are attached to
bilirubin with glycosidic ester bond bilirubin bisglucuronide
• conjugated bilirubin is soluble in water (bile, plasma, urine)
• conj. bilirubin is excreted with bile into intestine, where it is
deconjugated and hydrogenated by microflora urobilinogens,
they are partially absorbed by v. portae and taken up by liver
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Laboratory findings in three types
of hyperbilirubinemia
Hyperbilirubinemia Blood Urine
Hemolytic
Hepatic
Obstruction
↑↑ unconjug.
↑↑ both types
↑↑ conjug.
-
↑ conjug.
↑ conjug.
Normal concentration of bilirubine in blood
total bilirubine: 5-20 μmol/l
unconjugated up to: 12 μmol/l
conjugated up to: 5 μmol/l
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Greek word ξένος [xenos] means stranger
• Xenobiotics do not normally occur in human body
• Chemical industry – produces synthetic compounds which do
not occur in nature (plastics, pesticides, pigments, food
additives) and various pollutans (as side products)
• Pharmaceutical industry – produces drugs (medications) of
synthetic origine or isolated from plants/animals/fungi/bacteria
Biotransformation of xenobiotics
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Biotransformation of xenobiotics in cells
• two phases of biotransformations
• xenobiotics becomes more polar
• they are easily excreted from body (urine, bile - stool)
If not biotransformed very hydrophobic xenobiotics
would persist indefinitely in body fat !!!
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I. Phase of biotransformation
Reaction Xenobiotic (example)
Hydroxylation
Sulfooxidation
Dehydrogenation
Reduction
Hydrolysis
aromatic hydrocarbons
disulfides (R-S-R)
alcohols
nitro compounds (R-NO2)
esters
Reactions occur mainly in ER, some in cytosol
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Enzymes of I. phase are rather non-specific
• great advantage for human body !!
• monooxygenases (cytochrome P-450)
• flavine monooxygenases
• peroxidases
• hydrolases
• alcoholdehydrogenases and other ...
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Cytochrome P-450 (CYP)
• the group of hem enzymes (cca 150 isoforms)
• many of them are inducible
• occur in most tissues (except of muscles and RBC)
• mainly in liver
Abbreviation: P = pigment, 450 = wave lenght (nm), at which these
enzymes exhibit intensive absorption after binding CO
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Mechanism of cytochrome reaction
• CYP catalyzes hydroxylation (R-H R-OH )
• substrate reacts with O2
• monooxygenase = from O2 one atom O is inserted into
substrate (between carbon and hydrogen atom)
• the second O atom makes H2O, 2H come from NADPH+H+
• dioxygen is reduced to -OH group and water
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General scheme of hydroxylation
R-H + O2 + NADPH + H+ R-OH + H2O + NADP+
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A more detailed scheme of hydroxylation
NADP+
FAD
FADH2
Fe++
hem
Fe+++
hem
NADPH H++
2 H+
cyt. reduktasa cyt P-450
RH
R OH
O2
H2O
The system of cytochrome P-450 is composed from:
• two enzymes (cytochrome reductase, cytochrome P-450)
• three cofactors (NADPH, FAD, hem)
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Main isoforms of cytochrom P-450
CYP Substrate Inducer Inhibitor
CYP1A2
CYP2A6
CYP2C9
CYP2C19
CYP2D6
CYP2E1
CYP3A4
theophylline
methoxyflurane
ibuprofen
omeprazole
codeine
halothane
diazepam*
cigarette smoke
phenobarbital
phenobarbital
phenobarbital
rifampicine
alcohol
phenobarbital
erythromycine
methoxsalem
sulfaphenazole
teniposide
quinidine
disulfiram
grapefruit
the most abundantisoform
* and cca 120 other medicaments
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Induction and inhibiton of CYP 450
• some xenobiotics trigger induction of CYP synthesis
metabolic capacity of CYP increases
• if concurrently aplied inducer + medicament metabolized with
the same CYP isoform remedy is catabolized faster
is less effective
-------------------------------------------------------------------------------
• some xenobiotics are inhibitors of CYP
• if concurrently aplied inhibitor + medicament metabolized with
the same CYP isoform remedy is catabolized more slowly
higher concentration in blood adverse effects/overdosing
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Biotransformation of benzene
H
hydroxylace (CYP 450)
OH
Chronic benzene exposition can be proved by the detection of
phenol in urine (workers in chemical industry, sniffers)
hydroxylation
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Biotransformation of polycyclic aromatic
hydrocarbons (PAH)
Oepoxid OH
HO
H2O
OH
HO
O
dihydrodiol
vazba na DNA, mutace
nádory (kůže, plíce)
benzo[a]pyren
tumors (skin, lungs)
binding to DNA, mutation
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II. Phase of biotransformation
• conjugation – synthetic character
• xenobiotic after I. phase reacts with conjugation reagent
• the product is more polar – easily excreated by urine
• conjugation reactions are endergonnic – they require energy
• reagent or xenobiotic has to be activated
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Overview of conjugation reactions
Conjugation Reagent Group in xenobiotic
Glucuronidation
Sulfatation
Methylation
Acetylation
By GSH
By aminoacid
UDP-glucuronate
PAPS
SAM
acetyl-CoA
glutathione
glycine, taurine
-OH, -COOH, -NH2
-OH, -NH2, -SH
-OH, -NH2
-OH, -NH2
Ar-halogen
-COOH
GSH = glutathione, PAPS = phosphoadenosine phosphosulfate
SAM = S-adenosyl methionine
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Biosynthesis of UDP-glucuronate
O
OHOH
OH
O
CH2OP
H
O
OOH
OH
O
CH2HO
PH
O
OOH
OH
O
CH2HO
UDPH
UTP
glukosa-6-P glukosa-1-P UDP-glukosa
H
O
OOH
OH
O
C
UDP
OO NAD+
H2ONAD
+
glukosiduronáty
UDP-glukuronát
glucose-6-P glucose-1-P UDP-glucose
UDP-glucuronate
glucuronides
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The structure of UDP-glucuronate
N
OHOH
O
NH
O
O
OP
O
O
O
PO
O
OO
OH
O
COO
HH
N-glycosidic bondO-glycosidic bond
of ester type
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Glucuronides are the most abundant conjugates
• O-glucuronides
ether type (Ar-O-glucuronide, R-O-glucuronide)
ester type (Ar-COO-glucuronide)
• N-, S-glucuronides
• exogen. substrates: arom. amines, amphetamines,
salicylic acid, drugs, flavonoids …
• endogenous substrates: bilirubin, steroids
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Biotransformation of amphetamine
CH2 CH NH2
CH3
CH2 CH NH2
CH3
HO
CH2 CH NH2
CH3
OO
OHHOHO
HOOC
I. fáze
II. fáze
Example
ether type glucuronide
I. phase - hydroxylation
II. phase – conjugation with UDP-glucuronate
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PAPS is sulfatation reagentphospho adenosine phospho sulfate
O
OHO
O
P
PO
O
OSO
O
O
O
O
O
N
N
N
N
NH2
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The conjugation reactions of phenol
konjugace
O glukuronát O sulfát
H
hydroxylace (CYP 450)
OH
glucuronide sulfate
conjugation
hydroxylation
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Glutathione (GSH)
HOOCN
N COOH
O
H
CH2
SH
O
H
NH2
R-X + GSH R-SG + XH
R-X halogen alkanes (arenes)
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Mercapturic acids are final products of GSH conjugation
GSH
Glu
SCH2 CH COOH
NH
CO CH3
CH3CO SCoA
HS CoA
Gly+
N-acetyl-S-phenylcystein
(mercapturic acid)
urine
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Conjugation with aminoacids
• glycine, taurine
• xenobiotics with -COOH groups
• the products of conjugation are amides
• endogenous substrates – bile acids
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Biotransformation in toluene sniffers
CH3 CH2OH COOH
toluen benzylalkohol benzoová kys.
C
OH
O glycin
C
NH
O
CH2 C
OH
O
benzoová kys. hippurová kyselina(N-benzoylglycin)
toluene benzyl alcohol benzoic acid
benzoic acid
glycine
hippuric acid
(N-benzoylglycine)
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Main path of ethanol biotransformation occurs in liver cytosol
H3C C
H
H
O
H
+ NAD H3C C
H
O+
alkoholdehydrogenasa
aldehyddehydrogenasa
+ H2O H3C C
OH
H
O
H
H3C C
OH
ONAD- 2H
NADH+H
H3C C
H
O
acetaldehyd
aldehyd-hydrát octová kyselina
acetaldehyd dehydrogenase
alcohol dehydrogenase (ADH)
acetaldehyde
acetaldehyde hydrate acetic acid
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Alternative pathway of alcohol biotransformation
occurs in endoplasmic reticulum
MEOS (microsomal ethanol oxidizing system, CYP2E1)
CH3-CH2-OH + O2 + NADPH+H+ CH3-CH=O + 2 H2O + NADP+
activated at higher consumption of alcohol = higher blood level of alcohol
(> 0,5 ‰) - chronic alcoholics
increased production of acetaldehyde
‰ = per mille = 1/1000
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Q.
What are the main metabolic consequences of ethanol metabolism?
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Metabolic consequences of EtOH biotransformation
Ethanol
ADH
MEOS
acetaldehydepart. soluble in membrane
PL
toxic efects on CNS
adducts with proteins, NA, biog. amines
acetate
acetyl-CoA
FA synthesis liver steatosis
ADH
excess of NADH in cytosol
reoxidation by pyruvate
lactoacidosis
see p. 125
various products
causing hangover
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Nicotine - the main alkaloid of tobacco
N
N
CH3
3-(1-methylpyrrolidin-2-yl)pyridine
On cigarette box:
Nicotine: 0.9 mg/cig.
Tar: 11 mg/cig.
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Cigarette smoke contains a number of different compounds
• free nicotine – binds to nicotine receptors in brain and other
tissues (see page 135)
• CO – binds to hemoglobin carbonylhemoglobin
• nitrogen oxides – can generate free radicals
• polycyclic aromatic hydrocarbons (PAH)
(pyrene, chrysene), main components of tar, attack and
damage DNA, carcinogens
• other substances (N2, CO2, HCN, CH4, terpenes, esters …)
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Biotransformation of nicotine
N
NCH3
N
NH
N
NCH3
OH
N
NCH3
O
nikotin
nornikotin 5-hydroxynikotin
kotinin
nikotin-N-glukuronát
kotinin-N-glukuronát
Example
nicotine
nicotine-N-glucuronide
nornicotine5-hydroxynicotine
cotinine
cotinine-N-glucuronide
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Main pathways of paracetamol biotransformation
HN
CCH3
O
OH
PAPS
HN
CCH3
O
OS
O
O
O
UDP-glukuronát
HN
CCH3
O
OOOOC
HO OHHO
paracetamol N-(4-
hydroxyphenyl)acetamide
UDP-glucuronate
two types of conjugation
over the counter analgetic, antipyretic
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Side pathway of paracetamol biotransformation leads to hepatotoxic quinonimine
HN
CCH3
O
OH
cyt P-450
NC
CH3
O
O
N-acetylbenzochinonimin (hepatotoxický)
NADPH H+ O2+ +
NADP+ H2O+ 2
paracetamol
danger upon overdosing
danger in alcoholics
CYPE21
induced by alcohol
N-acetylbenzoquinonimine
hepatotoxic
causes liver necrosis
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Biotransformation of acetylsalicylic acid
COOH
OCOCH3esterasa
COOH
OH
salicylová kys.
COOH
OH
HO
cyt P-450
gentisová kys.
UDP-glukuronátsalicyl(acyl)-glukosiduronátsalicyl(fenol)-glukosiduronát
glycin
glycin
salicyloyl-glycin
gentisoyl-glycin
esterase
salicylic acid
gentisic acid
UDP-glucuronate
glycine
glycine
various conjugates
various conjugates
over the counter analgetic, antipyretic
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Selected biochemical markers of liver damage
Analyt (serum) Reference values Change
ALT
GMD
GMT
Bilirubin
Urobilinogens (urine)
------------------------------
Pseudocholinesterase
Urea
Albumin
0,1 - 0,8 kat/l
0,1 - 0,7 kat/l
0,1 - 0,7 kat/l
5 - 20 mol/l
up to 17 mol/l
65 - 200 kat/l
3 - 8 mmol/l
35 - 53 g/l