Metabolism of
xenobiotics
Xenobiotics-biotransformation 1
XENOBIOTICS
= compounds foreign to the body
1. ENTRANCE TO THE BODY
→digestive tract → blood → LIVER
→lungs → blood
→skin → blood
Xenobiotics are metabolized at the place of
„their entrance or exit“
Xenobiotics-biotransformation 2
2. BLOOD TRANSPORT
! chemical nature of the xenobiotic !
hydrophilic (polar)
→ water soluble
→ difficult transport through membranes
→ rapidly eliminated with the urine
Xenobiotics-biotransformation 3
lipophilic (nonpolar, hydrophobic)
→ poorly soluble in water
→ need a blood transporter (albumin)
→ freely diffuse through membranes
→ can be stored in membranes
→ slowly eliminated from the body
2. BLOOD TRANSPORT
! chemical nature of the xenobiotic !
Xenobiotics-biotransformation 4
Xenobiotics bound to transport proteins
→ the binding is reversible
→ ionic and hydrophobic interactions
→ competition of compounds
→ only free fraction of the xenobiotic is
biologically active
→ the binding to proteins decreases
elimination
of the xenobiotic from the body
Xenobiotics-biotransformation 5
Metabolism of xenobiotics can lead to
a) lowering their toxicity
b) increasing their toxicity
c) their bioactivation
d) increasing their water solubility
Xenobiotics-biotransformation 6
TEST
3. FATE OF XENOBIOTICS
1) utilizable substances can enter the body´s
intermediary metabolism (e.g. ethanol →
energy)
2) unutilizable substances are transformed to
more water soluble products and excreted with
the
→ urine (small molecules: to Mr = 300)
→ bile → stool (larger molecules)
Xenobiotics-biotransformation 7
TEST
3. FATE OF XENOBIOTICS
BIOTRANSFORMATION
TEST
Xenobiotics-biotransformation 8
Phase I- biotransformation
• localization
- the liver - membranes of ER, cytoplasm
- other tissues - lungs, intestine, skin, kidneys
• enzymes
- hydrolases (esterases, peptidases, ...)
- monooxygenases (= hydroxylases, cytochrome P450
= Mixed Function Oxidases = MFO)
Xenobiotics-biotransformation 9
TEST
• properties of the enzymes
- metabolism of endogenic substances
- broad substrate specificity
-inducibility (e.g. cyt P-450)
• reactions
- hydrolysis
- oxidation (e.g. hydroxylation, epoxidation)
- oxidative cleavage: e.g. dealkylation, deamination
- reduction
- methylation
Xenobiotics-biotransformation 10
TEST
Xenobiotics-biotransformation 11
Example of a reaction catalyzed by a hydrolase
Xenobiotics-biotransformation 12
Xenobiotics-biotransformation 13
TEST
Xenobiotics-biotransformation 14
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Xenobiotics-biotransformation 16
TEST
Xenobiotics-biotransformation 17
Xenobiotics-biotransformation 18
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Summary BIOTRANSFORMATION
1. a foreign substance including a polar functional
group
- original molecule
- or product of the Phase I.
(biotransformation)
2. activation of a conjugation endogenic substance
3. formation of a conjugate
4. excretion from the body
Xenobiotics-biotransformation 24
The metabolism proceed mostly
in the LIVER
Biotransformation does not mean
detoxification in all cases,
it can also increase the biological
activity!
(see indirect carcinogens)
Xenobiotics-biotransformation 25
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Cytochrome P-450
a) is a hemoprotein
b) is disolved in a cytoplasm
c) needs NADPH
d) participates in steroid
metabolism
Xenobiotics-biotransformation 30
TEST
Choose correct statement(s) about
biotransformations:
a) a hydrocarbon can be oxidized to an alcohol
b) an ester can be hydrolyzed to 2 alcohols
c) an aldehyde can be reduced to a carboxylic
acid
d) a carbonyl compound can be reduced to an
alcohol
Xenobiotics-biotransformation 31
e) an unsaturated or an aromatic hydrocarbon
can be transformed to an epoxide
f) an amide bond can be hydrolyzed to an acid
and an amine
g) benzoic acid can be transformed to hippuric
acid
h) UDP-glucuronate can be formed by
reduction of UDP-glc
Xenobiotics-biotransformation 32
Choose correct statement(s) about
conjugation reactions:
a) UDP-glucuronyl transferase synthetizes
glucuronides
b) PAPS is an active form of sulfuric acid
c) SAM is a derivative of methionine
d) glutathione contains 3 peptide bonds
Xenobiotics-biotransformation 33
Xenobiotics-biotransformation 34
Examples from metabolism of xenobiotics
a) nonpolar acetylsalicylic acid
• an active substance of Aspirin
• irreversible inhibition of synthesis of PG, PGI and TX
(cycloxygenase)
• bound to plasma proteins
• hydrolyzis of its ester bond (intesine, blood)
• conjugation in the liver with glycine → salicyluric acid
• excretion of the conjugate with urine
Xenobiotics-biotransformation 35
Examples from metabolism of xenobiotics
b) polar alcohols
ETHANOL
• absorbed in the stomach
• 10 % ecreted with the urine, breath, perspiration
• 90 % metabolized (mainly in the liver)
• oxidation: ethanol → acetaldehyde → acetic acid
• enzymes:
- alcohol dehydrogenase (cytoplasm, NAD + )
- aldehyde dehydrogenase (mitochondria, NAD + )
- or cyt P450 (MEOS) → oxidative stress
Xenobiotics-biotransformation 36
• excess of NADH
- inhibition of beta-oxidation and citrate cycle
- inhibition of gluconeogenesis
• acetaldehyde can damage proteins
• acetic acid metabolized mainly in the heart:
acetyl-CoA → citrate cycle, RCH → CO 2 , H 2 O
• acetate, lactate → metabolic acidosis
• accumulation of TAG in the liver
Xenobiotics-biotransformation 37
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METHANOL
• lower narcotic effect than ethanol
• slower excretion from the body → longer drunkenness
• metabolized by the same enzymes as ethanol
• causes harder sickness (formaldehyde)
• serious intoxication: 5 – 10 ml (lethal dose  30 ml)
• no symptoms immediately after drunkenness (6 – 30 h.)
• headache, pain in back, loss of sight
• metabolic acidosis
• therapy: ethanolemia  1 ‰ (1 - 2 days), liquids
Examples from metabolism of xenobiotics
b) polar alcohols
Xenobiotics-biotransformation 41
Ethanol
a) can be reduced to CH 3 CHO
b) can be metabolized by cyt P450
c) is a secondary alcohol
d) consumes NADH if metabolized
Xenobiotics-biotransformation 42
Increased ratio of NADH / NAD +
a) activates conversion of lactate
to pyruvate
b) inhibits citrate cycle
c) activates -oxidation
d) inhibits gluconeogenesis
Xenobiotics-biotransformation 43