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Xenobiotics ( Xenos = strange) are Xenobiotics ( Xenos = strange) are compounds that are foreign to the compounds that are foreign to the body.body.
It includes drugs, food additives, It includes drugs, food additives, pollutants etc.pollutants etc.
Understanding how xenobiotics are Understanding how xenobiotics are handled at the cellular level is handled at the cellular level is important in learning how to cope important in learning how to cope with the chemical attack.with the chemical attack.
The goal of xenobiotics metabolism is make xenobiotics less poisonous or nontoxic metabolite.
Activities of xenobiotics metabolism Activities of xenobiotics metabolism affected by species, genetic factors, affected by species, genetic factors, gendergender, age., age.
Intake phenobarbital or certain Intake phenobarbital or certain hydrocarbons can cause enzyme hydrocarbons can cause enzyme induction.induction.
BLOOD
XENOBIOTIC
BIOTRANS-FORMATION
EX
CR
ET
ION
DNAdamage
Somaticeffect
Detoxification
ActivationNon-toxicmetabolite
Toxicmetabolite
DefinitionBiotransformation is the sum of all processes,whereby a compound is transformed chemicallywithin a living organism
1. Xenobiotik hidrofilik masuk ke dalam sel pada kisi membran hepatosit melalui sistem transpor menggunakan protein karier.
2. Xenobiotik lipofilik (hampir 70-80%); mudah larut di dalam pelarut organik juga fosfolipid lapis ganda ( bilayer) dari membran sel sehingga tidak mengalami halangan yang berarti untuk berinteraksi dengan sel atau organel lainnya mengikuti hukum difusi non ionik.
Bound
Free
Bound
Free
Bound
Free
Target organ
Depot
Absorption
Excretion
Adipose tissuesInert membranesLipoprotein micellsLysosomesSkeleton (endo or exo)
UrineFaeces (gall)Lungs or gillsSecretion from surface
1. Biotransformasi : a. Reaksi melalui 2 fase b. Adaptasi enzimatik
2. Detoksifikasi amonia dan netralisasi bikarbonat a. Siklus Urea / Siklus Glutamin
b. Netralisasi bikarbonat
3. Degradasi Alkohol
4. Sistem Retikuloendotelial
5. Pemusnahan Radikal Bebas dan Antioksidan
Merupakan perubahan di dalam substansi biokimia melalui proses auto metabolik.
Proses biotransformasi / katabolisme xenobiotik berlangsung dalam 2 fase
yaitu; a. Fase 1 : Pengaktifan/ insersi gugus reaktif ke dalam
molekul substansi seperti lipofilik yang terlarut di dalam
air. Reaksi penting: oksidasi, reduksi, hidrolisis.
b. Fase 2 : Metabolit fase 1 mengalami konjugasi dengan substansi endogenus melalui transferasi
spesifik.
The overall purpose of the two phThe overall purpose of the two phasasee
is to increase their water is to increase their water solubility( polarity) and thus excretion solubility( polarity) and thus excretion from the body.from the body.
XenobiXenobiootics are protics are pro--drugs or prodrugs or pro--carcinogens.carcinogens.
Detoxification is usually used as terms Detoxification is usually used as terms to metabolism of xenobiotics.to metabolism of xenobiotics.
Terdapat 4 Mekanisme yang melibatkan adaptasi enzim:
1. Penginduksian Enzim
2. Penghambatan Enzim
3. Pengaktifan dan inaktifasi enzim
4. Reduksi di dalam perubahan enzim
Outline of metabolic activation and detoxification pathways
Enzyme Phase I Phase II
Types of reactions HydrolysisOxidationReduction
Conjugations
Increase inhydrophilicity
Small Large
General mechanism Exposes functionalgroup
Polar compound addedto functional group
Consquences May result inmetabolic activation
Facilitates excretion
XENOBIOTICPRIMARYPRODUCT
SECUNDARYPRODUCT
Expose or addfunctional group
OxidationReductionHydrolysis
PHASE I PHASE II
EXCRETION
Conjugation
LIPOPHILIC HYDROPHILIC
Phase I and phase II reactions
CONJUGATION REACTIONCONJUGATION REACTION
GlucuronidationGlucuronidation SulfationSulfation Conjugation with glutathioneConjugation with glutathione Acetylation e.g. in INH( isohydrazid)Acetylation e.g. in INH( isohydrazid) Methylation Methylation
Important phase I enzymes
Enzyme Co-factor Substrate
Mixed-function oxidases NADPH Most lipophilic substances(cytochrome P-450) (NADH) with M.wt < 800
Carboxyl esterases Unknown Lipophilic carboxyl esters
’A’ esterases Ca++ Organophosphate esteresEpoxide hydrolases Unknown Organic epoxids
Reduktases NADH Organic nitrous compoundsNADPH Organic halogens
Hemoprotein, like hemoglobin.Hemoprotein, like hemoglobin. Widely distributed across species.Widely distributed across species. Present in highest amount in liver and Present in highest amount in liver and
small intestines, mainly in the membranes small intestines, mainly in the membranes of the smooth endoplasmic reticulum.of the smooth endoplasmic reticulum.
Substrate speSubstrate specciificificity.ty. NADPH is involved in reaction mechanism NADPH is involved in reaction mechanism
in cyt P450.in cyt P450. Lipids also components of cyt P450 Lipids also components of cyt P450
system.system. Most of cyt P450 are inducible.Most of cyt P450 are inducible.
Certain isoforms of cyt P450 involved Certain isoforms of cyt P450 involved in metabolism of PAH( polycyclic in metabolism of PAH( polycyclic aromatic hydrocarbons) and called aromatic hydrocarbons) and called AHH( aromatic hydrocarbon AHH( aromatic hydrocarbon hydroxylases).hydroxylases).
Certain cyt P450 exist in polymorphic Certain cyt P450 exist in polymorphic forms.forms.
P-450 system in the endoplasmic reticulum
REDUCTASE
P-450P-450
Xenobiotic
NADPH
NADP+
Fp oxidized
Fp reduced
(RH)-P450-(Fe2+)
(RH)-P450-(Fe3+)
(RH)-P450-(Fe2+) ·O2
P450 (Fe3+)
O2
RH
ROH
+H2O
e-
e-
Cytochrome P-450’s catalytic cycle
CYT P- 450
Fe3+ Fe3+
NADPH
NADP
CYT P-450 reductase
+e-
Fe2+
O2
Fe2+
e-NADPH
NADP
Fe3+
H2O
Fe3+
HC(inducer)
Ah receptor-hsp90
HC
P450 mRNAP450 protein
• Bioactivation• Detoxification
Toxicity
Elimination
Cell
HC-AhR
hsp90
HC-AhR
XRE
P450 gen
Nucleus
Induction of cytochrome P-450
HC: Hydrocarbon (inducer)XRC: Regulator gene (stimulates transcription of P-450 gene)
Aliphatic hydroxylation
Aromatic hydroxylation
R R OH
R - CH CH - R’ R - CH - CH - R’
Epoxidation O
N-, O-, or S-dealkylation
R - (N, O, S) - CH3H
N - hydroxylation
Deamination
R - C - H + NH3 O
OO
R - NH - C – CH3 R - NOH - C – CH3
R - C - H R - C OH R - C -H + HXOX X
H H
R - S - R’ R - S - R’
Sulphur oxidation
S
R1R2P - X R1R2P - X + S
ODe-sulphurnation
Oxidative dehalogenation
Examples of oxidations catalysed by P-450
R - CH2 – CH2 – CH3 R – CH2 – CHOH – CH3
R – (NH2, OH, SH) + CH2O
R – CH2 – NH2