Xenobiotics ( Xenos = strange) are compounds that are foreign to the body.

It includes drugs, food additives, pollutants etc. Understanding how xenobiotics are handled at the cellular level is important in learning how to cope with the chemical attack.
The goal of xenobiotics metabolism is make xenobiotics less poisonous or nontoxic

Activities of xenobiotics metabolism affected by species, genetic factors, gender, age. Intake phenobarbital or certain hydrocarbons can cause enzyme induction.

XENOBIOTIC BLOOD Somatic effect

EXCRETION

BIOTRANSFORMATION DNA damage

Non-toxic metabolite Activation Detoxification Toxic metabolite

Definition
Biotransformation is the sum of all processes, whereby a compound is transformed chemically within 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.

Absorption Target organ

Bound Bound

Free Bound

Free

Free
Depot Adipose tissues Inert membranes Lipoprotein micells Lysosomes Skeleton (endo or exo) Excretion Urine Faeces (gall) Lungs or gills Secretion 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 phase is to increase their water solubility( polarity) and thus excretion from the body. Xenobiotics are pro-drugs or procarcinogens. Detoxification is usually used as terms 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 Types of reactions

Phase I Hydrolysis Oxidation Reduction Small Exposes functional group May result in metabolic activation

Phase II Conjugations

Increase in hydrophilicity General mechanism Consquences

Large Polar compound added to functional group Facilitates excretion

Phase I and phase II reactions

PHASE I

PHASE II

Expose or add functional group XENOBIOTIC Oxidation Reduction Hydrolysis PRIMARY PRODUCT Conjugation SECUNDARY PRODUCT

EXCRETION

LIPOPHILIC

HYDROPHILIC

CONJUGATION REACTION
Glucuronidation Sulfation Conjugation with glutathione Acetylation e.g. in INH( isohydrazid) 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 A esterases Ca++ Epoxide hydrolases Unknown Reduktases NADH NADPH Lipophilic carboxyl esters Organophosphate esteres Organic epoxids Organic nitrous compounds Organic halogens

Hemoprotein, like hemoglobin. Widely distributed across species. Present in highest amount in liver and small intestines, mainly in the membranes of the smooth endoplasmic reticulum. Substrate specificity. NADPH is involved in reaction mechanism in cyt P450. Lipids also components of cyt P450 system. Most of cyt P450 are inducible.

Certain isoforms of cyt P450 involved in metabolism of PAH( polycyclic aromatic hydrocarbons) and called AHH( aromatic hydrocarbon hydroxylases). Certain cyt P450 exist in polymorphic forms.

P-450 system in the endoplasmic reticulum

Cytochrome P-450s catalytic cycle

Xenobiotic
Fe3+ Fe3+

CYT P- 450 NADPH

+

e-

NADP
Fe3+

CYT P-450 reductase

Fe2+

H2O
Fe3+

O2
NADPH eNADP
O2 e RH

Fe2+

NADPH e NADP+

Fp oxidized Fp reduced

(RH)-P450-(Fe2+)

(RH)-P450-(Fe2+) O2

ROH

+
P450 (Fe3+) H2O

(RH)-P450-(Fe3+)

Induction of cytochrome P-450

Ah receptor-hsp90 HC (inducer) HC

Cell

Nucleus
HC-AhR hsp90 XRE HC-AhR P450 gen

P450 protein Bioactivation Detoxification Toxicity

P450 mRNA

Elimination

HC: Hydrocarbon (inducer) XRC: Regulator gene (stimulates transcription of P-450 gene)

Examples of oxidations catalysed by P-450

Aliphatic hydroxylation Sulphur oxidation R - CH2 CH2 CH3 R CH2 CHOH CH3R - S - R R - S - R Aromatic hydroxylation R Epoxidation R - CH CH - R R OH O R - CH - CH - R De-sulphurnation S R1R2P - X

O
1 2P - X + S R R

Oxidative dehalogenation X X R-C-H R - C OH H

O R - C -H + HX

N-, O-, or S-dealkylation H H 3 R - (N, O, S) - CH R (NH2, OH, SH) + CH2O Deamination R CH2 NH2 N - hydroxylation O R - NH - C CH3 O R - C - H + NH3 O R - NOH - C CH3