Biotransformation of xenobioticsBiotransformation of xenobiotics
Biochemistry II
Lecture 5 2008 (J.S.)
Xenobiotics are compounds present in the environment thatXenobiotics are compounds present in the environment that
cannot be used in normal biological processes – that are
foreign to the body.
Humans are subjected to exposure to various xenobiotics continually.Humans are subjected to exposure to various xenobiotics continually.
The principal classes of xenobiotics are drugs, food additives,
polycyclic aromatic hydrocarbons (PAH) formed by incomplete
combustion of organic compounds, or by smoking and roasting ofcombustion of organic compounds, or by smoking and roasting of
food, various pollutants – products of chemical industry (halogenderivatives
of organic compounds, pesticides), and some naturalderivatives of organic compounds, pesticides), and some natural
compounds of plant origin that are strange for animals (e.g.
alkaloids, spices).alkaloids, spices).
They enter the body usually by ingestion, inhalation, or penetrate
occasionally through the skin, sometimes inadvertently, or may beoccasionally through the skin, sometimes inadvertently, or may be
taken deliberately as drugs.
2
Most xenobiotics are hydrophobic (lipophilic) compoundsMost xenobiotics are hydrophobic (lipophilic) compounds
and this property enables their nonspecific penetration across
the phospholipid dilayer of plasmatic membranes.the phospholipid dilayer of plasmatic membranes.
The elimination of xenobiotics from the body depends on their
transformation to more hydrophilic compounds.transformation to more hydrophilic compounds.
The most hydrophobic xenobiotics, called persistent organic pollutants,
once they are released into the environment remain intact for long periods of
time. For example, polychlorinated biphenyls (PCBs), dioxins, insecticidestime. For example, polychlorinated biphenyls (PCBs), dioxins, insecticides
DDT, and dieldrin accumulate in the adipose tissue of living organisms, cannot
be excreted from the bodies, and are found at higher concentrations in thebe excreted from the bodies, and are found at higher concentrations in the
food chain.
The overall purpose of the biotransformation of xenobiotics is
to reduce their nonpolar character as far as possible.
The products of transformation are more polar, many of them
are soluble in water.are soluble in water.
Their excretion from the body is thus facilitated.
3
Under certain conditions, some cell-types become resistant to drugs that
were initially toxic to them. This phenomenon is called multidrug resistance,were initially toxic to them. This phenomenon is called multidrug resistance,
such cells are able to extrude drugs out of the cell before the drug can
exert its effects.exert its effects.
Those cells express a membrane protein that acts as and ATP-dependent
transporter of small molecules out of the cell. The protein is called MDR protein
(multidrug resistance protein) and it belongs to the family of proteins that have(multidrug resistance protein) and it belongs to the family of proteins that have
two characteristic ATP-binding domains (ATP-binding cassettes, ABCs).
Excretion of xenobiotics from the body
After chemical modification, the more hydrophilic compounds are
excreted into the urine, bile, sweat. They can also occur in the milk.
Excretion of xenobiotics from the body
excreted into the urine, bile, sweat. They can also occur in the milk.
Volatile products are breathed forth.
Under certain conditions, compounds excreted into the bile can undergo
deconjugation and absorption (the enterohepatic circulation).
4
Biotransformation of xenobioticsBiotransformation of xenobiotics
is located mostly in the liver
It proceeds in two phases:
Phase I - the polarity of the compound is increased by introducing aPhase I - the polarity of the compound is increased by introducing a
polar group (hydroxylation is a typical reaction), increase in polarity by
another way, or demasking a polar group (e.g., by hydrolysis of an ester
or dealkylation of an amide or ether).or dealkylation of an amide or ether).
The reactions take place predominantly on the membranes of
endoplasmic reticulum, some of them within the cytoplasm.endoplasmic reticulum, some of them within the cytoplasm.
The first phase reactions may convert some xenobiotics to the
compounds that are more biologically active than the xenobiotic itself.
Phase II – Cytoplasmic enzymes catalyze conjugation of the functional
groups introduced in the first phase reactions with a polar component
(glucuronate, sulfate, glycine, etc.). These products are mostly less
biologically active than the substrate drug, the xenobiotic is detoxified.
5
Example:
Biotransformation of amphetamineBiotransformation of amphetamine
amphetamine
Phase I reaction
Phase II reaction
Phase I reaction
4-hydroxyamphetamine
4-hydroxyamphetamine
4-O-glucosiduronate
Phase II reaction
4-hydroxynorephedrine
4-hydroxynorephedrine
Phase II reaction
6
4-hydroxynorephedrine
4-O-glucosiduronate
Reactions of biotransformation – phase I
Reaction Xenobiotic types
Hydroxylation
Dehydrogenation
aromatic systems (even heterocyclic)
alcohols, aldehydesDehydrogenation
Sulfooxidation
Reduction
alcohols, aldehydes
dialkyl sulfides (to sulfoxides))
nitro compounds (to amines)Reduction
O- and N-dealkylation
nitro compounds (to amines)
ethers (to hemiacetals),
sec. amines (to N-hemiacetals)
Hydrolysis
sec. amines (to N-hemiacetals)
esters
and others.and others.
7
The liver microsomal monooxygenases,The liver microsomal monooxygenases,
called also hydroxylating monooxygenases
or mixed-function oxidasesor mixed-function oxidases
are prominent enzymes catalyzing reactions of the phase I.
They act on an infinite range of different molecular types because ofThey act on an infinite range of different molecular types because of
having low substrate specificity.
There are two major groups of monooxygenases:There are two major groups of monooxygenases:
– monooxygenases that contain cytochrome P450, and
– flavin monooxygenases.– flavin monooxygenases.
Flavin monooxygenases
are important in biotransformation of drugs containing sulfurous andare important in biotransformation of drugs containing sulfurous and
nitrogenous groups on aromatic rings or heteroatoms (namely
antidepressants and antihistaminics), and of alkaloids.antidepressants and antihistaminics), and of alkaloids.
Typical products of the reactions catalyzed by flavin monooxygenases
are sulfoxides and nitroxides.
8
Cytochrome P450 monooxygenases
are the major monooxygenases of endoplasmic reticulum.
The abbreviation P450 is used because those enzymes can be
recognized, if they bind carbon monoxide, as pigments that have
Approximately 400 isoforms of these enzymes have been found in the
nature, over 30 isoforms in humans.
recognized, if they bind carbon monoxide, as pigments that have
a distinct band at 450 nm in their absorption spectra.
nature, over 30 isoforms in humans.
These haemoproteins are the most versatile biocatalysts known.
In addition to their high activity in the liver cells, they occur in nearly allIn addition to their high activity in the liver cells, they occur in nearly all
tissues, except for skeletal muscles and erythrocytes.
2 H+
FAD haem Fe2+NADPH + H+
2 H
substrate
RH
O
NADP+ FADH2 R–OH
O2
H2Ohaem Fe3+
flavoprotein
NADP FADH2
cytochrome P450
reductase
cytochrome P450
R–OH
hydroxylated
product
haem Fe
9
Cytochrome P450 monooxygenases transform also a large number of
compounds that are natural components of the body.
Let us recall hydroxylation of cholesterol, calciols, steroid hormones,
haemoxygenase in the haem catabolism, and also desaturation
of fatty acids.
Many of cytochrome P450 monooxygenases are inducible.
The hepatic synthesis of cyt P450 monooxygenases is increased by
of fatty acids.
The hepatic synthesis of cyt P450 monooxygenases is increased by
certain drugs and other xenobiotic agents.
If another xenobiotic, which is metabolized by the same isoform of the enzymeIf another xenobiotic, which is metabolized by the same isoform of the enzyme
and induces its synthesis, appears together with a needed drug in the body,
the rate of phase I reactions transforming the needed drug can be many times
higher during few days. Consequently, the biological effect of the drug is lower.higher during few days. Consequently, the biological effect of the drug is lower.
Some xenobiotics act as inhibitors of cyt P450 monooxygenases.
If an inhibitor is applied with a needed drug, the drug concentration in plasma is
higher than the usual one. The patient may be overdosed or unwanted side effects
can appear.
10
can appear.
Genetic polymorphism of cyt P450 monooxygenases
Allelic variation that effects the catalytic activity of monooxygenases will
Genetic polymorphism of cyt P450 monooxygenases
Allelic variation that effects the catalytic activity of monooxygenases will
also affect the pharmacologic activity of drugs.
Example of such polymorphism is that of the isoform CYP 2D6: there areExample of such polymorphism is that of the isoform CYP 2D6: there are
extensive metabolizers (most of normal population),
poor metabolizers (5 – 10 % of normal individuals), and
rapid metabolizers (individuals who rapidly metabolize debrisoquine as
well as a significant number of other commonly used drugs).
In the group of rapid metabolizers – the plasma levels of drugs are higherIn the group of rapid metabolizers – the plasma levels of drugs are higher
than expected, unwanted side effects are oft.
In the group of rapid metabolizers – lower drug plasma levels thanIn the group of rapid metabolizers – lower drug plasma levels than
expected after usual doses, the treatment is ineffective. To obtain
satisfactory results, the drug doses have to be higher than those used insatisfactory results, the drug doses have to be higher than those used in
extensive or poor metabolizers.
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The most important human cyt P450 monooxygenasesThe most important human cyt P450 monooxygenases
Selected examples of substrates and effectors:
CYP Typical substrate Inducer – example Inhibitor – example
Selected examples of substrates and effectors:
CYP 1A2 theophylline tobacco smoke erythromycin
CYP 2A6
CYP 2C9/19
methoxyflurane
ibuprofen
phenobarbital
phenobarbital
-
sulfaphenazole
CYP 2D6
CYP 2E1
codeine
alcohols, ethers
phenobarbital
rifampicin
ethanol
quinidine
disulfiramCYP 2E1
CYP 3A4
alcohols, ethers
diazepam
ethanol
phenobarbital
disulfiram
furanocoumarins
(in grapefruits)
Approximate fraction of total CYP activity: CYP 2C9/19 10 %
CYP 2D6 30 %
CYP 3D4 50 % (25 – 70 %)
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CYP 3D4 50 % (25 – 70 %)
Reactions of biotransformation – phase II
The reactionsThe reactions
– render xenobiotics even more water-soluble enabling excretion of them
into the urine or bile,into the urine or bile,
– convert the biologically active products of phase I reactions into less
active or inactive species.
Transferases (cytosolic or bound in membranes of ER) catalyze
conjugation, acetylation or methylation of the polar groups in products
of phase I reactions with another and mostly polar component.of phase I reactions with another and mostly polar component.
The reactions are endergonic, one of the reactants have to be activated.
Reaction type Reagent Group of the xenobiotic Bond type
Glucuronidation UDP-glucuronate -OH, -COOH, -NH2, -SH glycoside
Sulfation
Formation of sulfide
Formation of amide
PAPS
glutathione
glycine, taurine
-OH, -NH2 ester
electrophilic carbon sulfide
-COOH amideFormation of amide
Methylation
Acetylation
glycine, taurine
S-AM
acetyl-CoA
-COOH amide
phenolic -OH ether
-NH amide
13
Acetylation acetyl-CoA -NH2 amide
● Glucuronidation● Glucuronidation
A variety of UDP-glucuronosyltransferases are present in both cytosol andA variety of UDP-glucuronosyltransferases are present in both cytosol and
membranes of endoplasmic reticulum.
O-, N-, or S-glycosides are formed in the reaction of UDP-glucuronateO-, N-, or S-glycosides are formed in the reaction of UDP-glucuronate
with phenols, phenolic and benzoic acids, flavonoids, alcohols,
amphetamines, primary aromatic amines, thiophenols, as well as
endogenous bilirubin, many steroid compounds, catecholamines, etc.endogenous bilirubin, many steroid compounds, catecholamines, etc.
Example:Example:
phenol
UDP-glucuronate UDP phenyl ββββ-D-glucosiduronatephenol
UDP-glucuronate UDP phenyl ββββ-D-glucosiduronate
14
● Sulfation● Sulfation
Sulfotransferases bound in the membranes of endoplasmic reticulum
transfer the sulfate group from the universal sulfate donor
3‘-phosphoadenosyl-5‘-phosphosulfate (PAPS, "active sulfate")
to all types of phenols forming so sulfate esters orto all types of phenols forming so sulfate esters or
to aryl amines forming so N-sulfates (amides).
Steroid hormones and catecholamines are also
Example:
inactivated by sulfation.
Example:
phenol PAPS phenyl sulfate
PAPS
phenol PAPS phenyl sulfate
Ado-3´,5´,-bisphosphate
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Glutathione is an important intracellular
● Conjugation with glutathione
Glutathione is an important intracellular
reductant (antioxidant) and takes part
in transfer of amino acids acrossin transfer of amino acids across
plasmatic membranes.
GSH-transferases catalyze the transfer
of glutathione to a number xenobiotics
glutathione (GSH)
γ-glutamyl-cysteinyl-glycine
of glutathione to a number xenobiotics
(e.g. epoxides of aromatic hydrocarbons, aryl halides, electrophilic
carcinogens), which results in formation of aryl sulfides of glutathione.
γ-glutamyl-cysteinyl-glycine
carcinogens), which results in formation of aryl sulfides of glutathione.
Glutamyl and glycyl residues are removed from these conjugates by
hydrolysis, and the remaining cysteinyls are N-acetylated. The resulting
conjugates of N-acetylcysteine called mercapturic acids are excreted into
the urine.
CoA-SH
Example:
MOS
GSH
acetyl-S-CoA
CoA-SH
mercapturic acid
(N-acetyl-S-substituted cysteine)
Glu + Gly
epoxide
16
(N-acetyl-S-substituted cysteine)
● Conjugation with glycine
Arenecarboxylic acids, namely substituted benzoic acids, after activation
to acyl-CoAs give amides with glycine. The reaction is catalyzed by
cytosolic glycine-N-acyltransferases.cytosolic glycine-N-acyltransferases.
N-benzoylglycines are called hippuric acids.
Unsubstituted hippuric acid is present in the urine of healthy individuals –Unsubstituted hippuric acid is present in the urine of healthy individuals –
benzoic acid is a normal constituent of vegetables and also an additive
(fungicidal agent) to some foodstuffs. High urinary excretion of hippurate is
a marker of exposition to toluene, which undergoes oxidation to benzoate.
benzoic acid benzoyl-CoA
hippuric acid
(N-benzoylglycine)
glycine
(N-benzoylglycine)
CoA-SHCoA-SH
ATP
AMP
PPi
Bile acid, before secreted from the liver cells, are conjugated with glycine
in the same way (conjugated bile acids – glycocholate, chenodeoxycholate, etc.)
Taurine H N–CH -CH –SO – may also serve in conjugation, however
17
Taurine H2N–CH2-CH2–SO3
– may also serve in conjugation, however
conjugation of bile acids with taurine is of minor importance in humans.
● Acetylation
is the reaction, by which the biological effects of aromatic amines and
similar compounds are diminished. Acetyl-CoA is the donor of acetyl.
Isoniazid (INH, isonicotinic acid
hydrazide) is an effective
chemotherapeutic agent used in the
Example:
chemotherapeutic agent used in the
treatment of tuberculosis).
The genetic disposition to acetylate thisThe genetic disposition to acetylate this
type of xenobiotics with different
rates exists (slow and rapid acetylators).
acetyl-CoA
CoA-SH
● Methylation
of phenolic groups occurs oft in phase II of biotransformation.of phenolic groups occurs oft in phase II of biotransformation.
In spite a slight decrease in hydrophilicity of the products, the biological
effects that depend on the phenolic groups are supressed in this way.
The donor of methyl group is S-adenosyl methionine (S-AM), the reaction
is catalyzed by O-methyltransferases.
18
Catecholamines and estrogens are inactivated by O-methylation.
Benzene and other aromatic hydrocarbons
Biotransformation of selected compounds - examples
Benzene and other aromatic hydrocarbons
cyt P450 conjugation
phase I
cyt P450
phase II
conjugation
and
When the hydroxylating system
is overloaded, increased amounts
of reactive metabolites are formed:
High urinary excretion of phenol conjugates
at high professional exposition to benzene.of reactive metabolites are formed:
+
at high professional exposition to benzene.
covalent linking to cell macromolecules
•
+
GSH
GSH-transferase
covalent linking to cell macromolecules
– cell injury
– haptens → immune reaction – cell injury
– carcinogens, DNA mutations
epoxide
hydrolase
GSH
acetyl-S-CoA
CoA-SH
– carcinogens, DNA mutations
Glu + Gly
19mercapturic acids
Polycyclic aromatic hydrocarbons (PAH)Polycyclic aromatic hydrocarbons (PAH)
Sources of PAH:
– industrial combustion of fossil fuels, production of coke, asphalt,– industrial combustion of fossil fuels, production of coke, asphalt,
– combustion of wood (forest fires) and household rubbish,
– singed bread and pastry, smoking, grilling, barbecuing, and roasting of
foodstuffs, overheated fats and oils,foodstuffs, overheated fats and oils,
– soot, tobacco smoke.
Biotransformation of PAH is similar to simple aromatic hydrocarbons, e.g.:Biotransformation of PAH is similar to simple aromatic hydrocarbons, e.g.:
hydroxylation hydroxy derivatives that are mostly non-toxic
benzo[a]pyrene
hydroxylation
cyt P450
hydroxy derivatives that are mostly non-toxic
and eliminated after conjugation in phase II reactions
benzo[a]pyrene
epoxides that can give
dihydrodiols and, after a
further epoxidation,further epoxidation,
carbanion ions interacting
with DNA – carcinogens.
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Acetaminophen (p-acetaminophenol, paracetamol)
was prepared in 1893. Since approx. 1975, when it turned out that acetylsalicylic
acid may have some unwanted side-effects, serves acetaminophen as common
analgetic-antipyretic of the first choice.analgetic-antipyretic of the first choice.
Biotransformation:
The amide bond is not hydrolyzed!The amide bond is not hydrolyzed!
oxidation of only a small part to
N-acetyl-p-benzoquinoneimide (NAPQI),cyt P450
~ 3 % excreted
unchanged
into the urine
N-acetyl-p-benzoquinoneimide (NAPQI),
unless the conjugating capacity is exhausted
cyt P450
if conjugation capacityinto the urine
CONJUGATION
if conjugation capacity
is limited,
unwanted side effects:
– covalent bonding
GSH
– covalent bonding
to proteins,
– oxidation of –SH groups
in enzymes,
GSH
60 % as glucosiduronate
30 % as sulfate ester mercapturic acid
in enzymes,
– depletion of GSH,
– hepatotoxicity at
overdosing
21
30 % as sulfate ester mercapturic acid
overdosing
Acetylsalicylic acid (aspirin)
is an analgetic-antipyretic with antiinflammatory effect; minute doses inhibit
aggregation of blood platelets.
Biotransformation: acetylation of macromoleculesBiotransformation: acetylation of macromolecules
(acetylation of COX inhibits
the synthesis of prostaglandins)
UDP-glucuronate
esterase
UDP-glucuronate
salicyl glucosiduronate salicyloyl glucosiduronate
and
UDP
glycine
salicylate
cyt P450
salicyl glucosiduronate salicyloyl glucosiduronateUDP
glycine
cyt P450
o-hydroxyhippurate
(salicyloylglycine,
salicyluric acid)
glycine
2,5-dihydroxyhippurate
(gentisoylglycine,
gentisuric acid)
gentisate
quinone
(and products of its
oxidn.
salicyluric acid)
22
glycine gentisuric acid)(and products of its
polymerization)
Bromohexin is the prodrug of an expectorant ambroxol:Bromohexin is the prodrug of an expectorant ambroxol:
N-demethylation
hydroxylation
bromohexin
(prodrug)
ambroxol
(expectorant)
Antitussic codeine (3-O-methylmorphine) is transformed in part and slowly into
morphine:
(prodrug) (expectorant)
morphine:
O-demethylation
morphine
(analgesic, an addictive drug)
codeine
(antitussic)
23
(analgesic, an addictive drug)(antitussic)
It is proper to avoid application of too many different remedies together,It is proper to avoid application of too many different remedies together,
though their expected effects can be viewed as useful.
– Interactions between different drugs or their metabolites might– Interactions between different drugs or their metabolites might
cause enhancement or inhibition of pharmacological effects,
– the mixed type hydroxylases (cyt P450) are inducible, their activities
may increase many times in several days, so that the remediesmay increase many times in several days, so that the remedies
are less efficient,
– if the load of the detoxifying system is high, minor pathways of– if the load of the detoxifying system is high, minor pathways of
transformation can be utilized and produce unwanted side-effects
due to the formation of toxic metabolites,
– intensive conjugation with glutathione might result in depletion of this
important reductant in the cells, etc.
24
Biotransformation of ethanolBiotransformation of ethanol
occurs mainly in the liver.
Ethanol is oxidized to acetaldehyde and then to acetic acid.
There are three reactions that give acetaldehyde from ethanol.
– Cytosolic NAD+-dependent alcohol dehydrogenase is the most– Cytosolic NAD+-dependent alcohol dehydrogenase is the most
important, it functions even at low concentrations of ethanol
(Km = 2 mmol/l, i.e. 0,1 ‰):
CH3-CH2OH + NAD+ alcohol DH CH3-CH=O + NADH + H+
acetaldehyde
(Km = 2 mmol/l, i.e. 0,1 ‰):
– Microsomal ethanol oxidizing system (MEOS, which contains
CYP 2E1) is effective preferably at excess alcohol intake (at blood
concentrations higher than 0.2 - 0.5 ‰; K = 10 mmol/l):concentrations higher than 0.2 - 0.5 ‰; Km = 10 mmol/l):
CH3-CH2OH + O2 + NADPH + H+ CH3-CH=O + 2 H2O + NADP+
– In peroxisomes, catalase can catalyze oxidation of ethanol by hydrogen
peroxide:
CH -CH OH + H O CH -CH=O + 2 H O
25
CH3-CH2OH + H2O2 CH3-CH=O + 2 H2O
Aldehyde dehydrogenase catalyzes oxidation of acetaldehyde to
OH aldehyde DH
Aldehyde dehydrogenase catalyzes oxidation of acetaldehyde to
acetic acid:
OH
OH
acetaldehyde hydrate
CH3-CH=O + H2O CH3-CH CH3-COOH
acetate
aldehyde DH
NAD+ NADH + H+acetaldehyde acetateNAD NADH + H
Acetate is activated to acetyl-CoA.
In excessive alcohol intake, NAD+ is spent for dehydrogenation of ethanol
preferentially so that excess lactate (from pyruvate) is formed.
In the liver cells lacking in NAD+,In the liver cells lacking in NAD+,
gluconeogenesis is decreased (resulting in hypoglycaemia),
β-oxidation of fatty acids inhibited (liver steatosis),β-oxidation of fatty acids inhibited (liver steatosis),
increased ketogenesis (from acetate), and
because the rate of acetaldehyde oxidation is reduced,
the toxic effects of acetaldehyde are more pronounced.the toxic effects of acetaldehyde are more pronounced.
26
Consequences of drinking
ETHANOL
ADH / MEOS ADH + AldDH
acetaldehyde
(hangover)
interpolates
into membranes,
increased
high NADH/NAD+ ratio
increased
membrane fluidity
various adducts acetate
reoxidation of NADH
by pyruvate
AldDH
various adducts
with proteins,
nucleic acids.
biogenic amines
acetate
lactacidaemia
hypoglycaemia
CNS
immediate
toxic effects
biogenic amines
(alkaloids?) acetyl-CoA
hypoglycaemia
(inhibition of
gluconeogenesis
and β-oxidation of FA)toxic effects
fatty acid synthesis
(fatty liver)
and β-oxidation of FA)
social consequences
of chronic alcoholism
27
(fatty liver)of chronic alcoholism
Tests for detection of ethanol intake
Elevated blood levels of ethanol decrease due to its oxidation, ethanol is eliminated
from the body during several hours. γ-Glutamyltransferase (γγγγGT) in serum is
increased in chronic alcoholism oft, but this test is not specific.
New tests have been developed (unfortunately, they are not yet used commonly in
increased in chronic alcoholism oft, but this test is not specific.
New tests have been developed (unfortunately, they are not yet used commonly in
routine laboratory practice), which are able to detect not only when a person drank last
time, but also if the doses taken were moderate or excessive.
Ethyl glucosiduronate (EtG) increases in the blood synchronously with the decreaseEthyl glucosiduronate (EtG) increases in the blood synchronously with the decrease
of blood ethanol and can be detected (in the urine, too) after few days, even up to 5 days.
Fatty acids ethyl esters (FAEE) appear in the blood in 12 – 18 h after drinking and can
be detected even 24 h after alcohol in blood is no more increased. However, traces ofbe detected even 24 h after alcohol in blood is no more increased. However, traces of
FAEEs are deposited in hair for months and may serve as a measure of alcohol intake.
Phosphatidyl ethanol (PEth) is present in the blood of individuals, who have beenPhosphatidyl ethanol (PEth) is present in the blood of individuals, who have been
drinking moderate ethanol doses daily, in even 3 weeks after the last drink.
Carbohydrate-deficient transferrin (CDT). In the saccharidic component of each
transferrin molecules, there are 4 – 6 molecules of sialic acid. Drinking to excess disturbestransferrin molecules, there are 4 – 6 molecules of sialic acid. Drinking to excess disturbes
the process of transferrin glycosylation so that less sialylated forms of transferrin (with
only two or less sialyl residues per molecule, CDT) are detected in blood during
approximately 4 weeks after substantial alcohol intake.
28
approximately 4 weeks after substantial alcohol intake.