Metabolisme Xenobiotik Metabolisme Xenobiotik: Toxicants Biotrasformation
Metabolisme Xenobiotik Metabolisme Xenobiotik: Toxicants Biotrasformation
Metabolisme Xenobiotik Metabolisme Xenobiotik: Toxicants Biotrasformation
TOXICANTS
TOXICANTS BIOTRASFORMATION
BIOTRASFORMATION
Introduction
Arifah
Arifah Sri
Sri Wahyuni
Wahyuni
arifah.wahyuni@ums.ac.id
arifah.wahyuni@ums.ac.id
Learning Outcomes
1. Menjelaskan prinsip biotransformasi pada fase
toxicokinetik
2. Memahami biotransformasi pada eliminasi toxicant.
3. Membedakan rekasi Phase I & Phase II pada
biotransformasi.
4. Mengidentifikasi bioactivasi or toxikasi.
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XENOBIOTIK
Xenobiotik asal kata : xenos (Yunani)
berarti asing
Definisi: senyawa asing yang terdapat di
dalam tubuh (karsinogen kimiawi,
insektisida tertentu, obat, dll)
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BIOTRANSFORMASI
Eliminasi xenobiotik tergantung pada perubahan obat
menjadi metabolit yang larut air melalui biotransformation
Biotransformation changes the properties of a xenobiotic
usually from a lipophilic form (that favors absorption) to a
hydrophilic form (favoring excretion in the urine or bile).
The main goal of biotransformation is to increase the rate of
excretionof xenobiotics or drugs.
Metabolism - is “changed” so that it can be excreted
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Biotransformation:
Modification of the chemical structure of
parent compound in organism, catalysed
by enzymes
Metabolites with different potency
Most of enzymes bound in hepatocytes
The liver and the first pass metabolism
Lipophilic compounds – extensive metabolism
Polar metabolites – excreted by urine
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Elimination ways:
Urine – polar compounds
Feaces – lipophilic compounds
Lungs – gases, volatiles
Hair – deposits of basic
compounds above all
Saliva – hydrophilic/lipophilic
Sweat – hydrophilic/lipophilic
Major biotransformation sites
Extrahepatic microsomal
• Liver enzymes
(oxidation, conjugation)
• Other….
– kidneys Hepatic
– muscle microsomal
tissue enzymes
(oxidation,
– intestinal
conjugation)
wall
– lungs Hepatic non-
– skin microsomal enzymes
(acetylation,
– blood sulfation,GSH,
alcohol/aldehyde
dehydrogenase,
hydrolysis, ox/red)
Phase I
– functionalizati
on reactions
Phase II
– conjugation
reactions
Main ways of biotransformation of drugs
I phase II phase
• Oxydation: diazepam, • Conjugation with sulfate:
pentazocin, sydnocarb, morphin, paracetamol, isadrin
phenotiazin, phenobarbital, • Conjugation with glucuronic
aspirin, butadion, lidokain, acid: teturam, sulfonamides,
morphin, codein, ethanol, levomycetin, morphin
rifampicin • Conjugation with remains of -
• Reduction: hestagens, aminoacids: nicotinic acid,
metronidazol, nitrazepam, paracetamol
levomycetin, chlozepid • Acetylation: sulfonamides,
• Hydrolysis: levomycetin,
isoniasid, novocainamid
novocain, cocain, glycosides,
• Methylation: morphin, unitiol,
ditilin, novocainamid, xycain,
fentanyl ethionamid, noradrenalin
Phase I biotransformation reactions*
1. Microsomal:
1. CYP450 monooxygenases
2. Flavin monooxygenase
2. Non-microsomal
1. Alcohol dehydrogenase
2. Aldehyde dehydrogenase
3. Monoamine and diamine oxidases
3. Both
1. Esterases and Amidases
2. Prostaglandin synthase
3. Peroxidases
ROLE OF CYP ENZYMES IN HEPATIC
DRUG METABOLISM
CYP 2C19
11%
CYP 2C9
CYP 2C
14%
17% CYP2D6
OTHER 23%
36%
CYP 1A2
CYP 1A2
14%
12%
CYP2E1
CYP 3A4-5 CYP 3A4-5
5%
26% 33%
Participation of the CYP Enzymes in Metabolism of
Some Clinically Important Drugs
Species Differences
Phenylbutazone t 1/2
Rabbit 3 jam
Rat 6 jam
Guinea Pig 6 jam
Dog 6 jam
Human 3 hari
• Induction
– Two major categories of CYP inducers
• Phenobarbital is prototype of one group - enhances
metabolism of wide variety of substrates by causing
proliferation of SER and CYP in liver cells.
• Polycylic aromatic hydrocarbons are second type of
inducer (ex: benzo[a]pyrene).
– Orphan Nuclear Receptors (PXR, CAR) are
regulators of drug metabolizing gene expression
Why to care about biotransformation
Understanding of drug
effects
Development of a
toxicological method
Interpretation of
toxicological findings
Correct and effective
therapy, reduction of
adverse drug effects
M. Balíková: The Fate of Poison 28
Acetaminophen and p-Aminophenols
COCH3 COCH3
HN HN
NH2
OH
Acetaminophen, 1893
Acetominophen Metabolism
COCH3
HN
~60% ~35%
COCH3 OH
HN
COCH3
CYP2E1*
HN
CYP1A2
CYP3A11
O CO2H
O
COCH3
OH N O
HO SO3H
OH *induced by ethanol, isoniazi
Protein adducts, O
Oxidative stress NAPQI
Toxicity N-acetyl-p-benzoquinone imine
Acetaminophen Protein Adducts
COCH3 COCH3
HN N
CYPs
HS-Protein
OH O
H2N-Protein
S Protein NH Protein
O OH OH
COCH3 COCH3
HN N
CAR CYP2E1*
toxicity
PXR CYP3A11
OH O
Xenobiotics
COCH3 SH
HN
glu-cys-gly
oxidative stress
GLY mechanism ?
S CYS toxicity
OH GLU
Contoh Kasus
Pasien 12 th/pria, kulit putih diobati dengan
imipramine 'dosis rendah' untuk masalah perilaku dan
enuresis. Obat diresepkan selama 1 bulan.
Pada tiga minggu Donny mengeluhkan kelelahan,
kelemahan.
Pada akhir bulan pengobatan, pasien merasa kurang
sehat; kemudian dia mandi air hangat; namun setelah
itu malah ambruk dan mati