TOKSIKOLOGI DAN AGROMEDIS

Al MunawirFK UNIVERSITAS JEMBER

Toksikologi

• Ilmu ttg , deteksi, efek , dan mekanisme kerja racun atau zat kimia beracun.

• Racun dan obat…………beda dosis.

AGROMEDIS

• AGROMEDICINE• Pertanian, peternakan, perikanan.• KEDOKTERAN AGROINDUSTRI• KOMUNITAS AGROINDUSTRI• MEMECAHKAN MASALAH KEDOKTERAN DAN

KESEHATAN PADA MASYARAKAT AGROINDUSTRI PADA PASIEN SIMULASI DALAM KONTEKS PELAYANAN PRIMER DAN KEDOKTERAN KELUARGA

FAKULTAS KEDOKTERAN UNIV. JEMBER

• KOMISI PENGEMBANGAN AGROMEDIS• KOMISI PENDIDIKAN KEDOKTERAN• KOMISI KARYA TULIS ILMIAH• KOMISI BIMBINGAN DAN KONSELING• GUGUS PENJAMIN MUTU• KOMISI ETIK PENELITIAN KESEHATAN• KOMISI TEKNOLOGI INFORMASI• KOMISI KETRAMPILAN KLINIK

MASALAH AGROMEDIS:

• PERILAKU komunitas agroindustri• PESTISIDA (produk, tanah, air, udara)• 1500 macam pestisida yang tercatat• Produk pertanian hasil rekayasa genetik

Figure 8-1 Human exposure to pollutants. Pollutants contained in air, water, and soil are absorbed through the lungs, GI tract, and skin. In the body they may act at the site of absorption but are generally transported through the bloodstream to various organs, where they may be stored or metabolized. Metabolism of xenobiotics may result in the formation of water-

soluble compounds that are excreted or in activation of the agent, creating a toxic metabolite.

Downloaded from: StudentConsult (on 9 April 2013 03:17 AM)© 2005 Elsevier

Figure 8-2 Xenobiotic metabolism. Xenobiotics can be metabolized to nontoxic metabolites and eliminated from the body (detoxification). However, their metabolism may also result in activation of the chemical leading to formation of a reactive metabolite that is toxic to cellular components. If repair is not effective, short- and long-term effects develop. (Based on

Hodgson E: A Textbook of Modern Toxicology, 3rd ed. Fig. 1-1. Hoboken, New Jersey, John Wiley & Sons, 2004.)

Downloaded from: StudentConsult (on 9 April 2013 03:17 AM)© 2005 Elsevier

Peran CYPs enzymes subFamily

BiotransformationXenobiotic metabolism

“Essentials of Toxicology”

by Klaassen Curtis D. and Watkins John B Chapter 6

Biotransformation

• Water soluble xenobiotics are easier to eliminate ( t1/2)– Urine, feces but not exhalation– If within barrier, no out

• Multiple enzymes (families)– Constitutively expressed– Inducible– Broad specificity– Polymorphic (allelic variants)– Stereo-isomer specificity: 6-OH in hormones:

CYP2A1 6-OH CYP3A 6-OH

Biotransformation

Potentially toxic xenobiotic

Inactive metabolite

Relatively harmless

Reactive intermediate

DetoxificationMetabolic activation

Converting lipophilic to water soluble compounds

Xenobiotic

Reactive intermediate

Conjugate

Phase I - Activation

Phase II - Conjugation

Excretion

Lipophilic

(non-polar)

Water soluble(polar)

Phase I

• introduction of functional group

• hydrophilicity increases slightly• may inactivate or activate original compound• major player is CYP or mixed function oxygenase (MFO)

system in conjunction with NAD(P)H• location of reactions is smooth endoplasmic reticulum

Phase II

• conjugation with endogenous molecules(GSH, glycine, cystein, glucuronic acid)

• hydrophilicity increases substantially• neutralization of active metabolic intermediates• facilitation of elimination • location of reactions is cytoplasm

Phase I reactions

Oxidation Hydroxylation (addition of -OH group) N- and O- Dealkylation (removal of -CH side chains) Deamination (removal of -NH side chains) Epoxidation (formation of epoxides) Oxygen addition (sulfoxidation, N-oxidation) Hydrogen removal

Reduction Hydrogen addition (unsaturated bonds to saturated) Donor molecules include GSH, FAD, NAD(P)H Oxygen removal

Hydrolysis Splitting of C-N-C (amide) and C-O-C (ester) bonds

OC C

OC

See also Chapter 6 of Casarett and Doull’s “Toxicology”

Table 6.1

epoxide

Biotransformation• Activation of xenobiotics is a key element

(e.g. benzene, vinyl chloride)– Reactive intermediates include epoxides and free

radical species (unpaired electrons) that are short-lived and hence highly reactive

– Protection is provided by • endogenous antioxidant substances, e.g. GSH• vitamins C and E• antioxidant enzymes, SOD, GPX, CAT in coupled reactions

– Antioxidant molecules are oxidized in the process but have the capacity to regenerate the reduced form from the oxidized - NAD(P)H is a key player

See also p. 40-44 of Casarett and Doull’s “Toxicology”

Cytochrome P450 (CYP) Mixed Function Oxidases (MFO)

• Located in many tissues but highly in liver ER• Human: 16 gene families• CYP 1,2,3 perform drug metabolism• >48 genes sequenced• Key forms: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1,

and CYP3A4• Highly inducible

– Alcohol CYP2E1– Dioxin/PCBs CYP1A– Barbiturates CYP2B

• CYP genes have multiple alleles (2D6 has 53, and 2E1 has 13)

The CYP-450 reaction cycleA

E

D

C

F

G(B)

Oxidation of vinyl chloride to an epoxide

Metabolic enzymes

1. Microsomal:1. CYP450 monooxygenases2. Flavin monooxygenase

2. Non-microsomal1. Alcohol dehydrogenase2. Aldehyde dehydrogenase3. Monoamine and diamine oxidases

3. Both1. Esterases and Amidases2. Prostaglandin synthase 3. Peroxidases

Cooxidation of acetaminophenby prostaglandin endoperoxide synthetase

Compare to fig. 6-2

Hydrolysis of esters and amides

Hydrolysis of organophosphates

Hydrolysis of epoxides

Stereoselectivehydroxylation

Metabolism of benzo(a)pyrene to 9,10 epoxide:Potent mutagen that binds DNA

Azo- and nitro- reduction

Flora action

Intestinal flora as part of biotransformation

reabsorption

Ready for elimination

Oxidation reactions

Benzene trasformation to leukemia-causing metabolite

Flavin mono-oxygenases(FMO) catalyzed reactions

Nitrogen compounds

Phase II reactions

• Glycoside conjugation - glucuronidation• Sulfate - sulfation• Glutathione (GSH)• Methylation• Acylation– Acetylation– Amino acid conjugation– Deacetylation

• Phosphate conjugation

Glucuronidation of phenol

Sulfation of phenol and toluene

GSH conjugation of acetaminophen

Glutathione

-glutamyl-cysteinyl-glycine

Active site of a GST:

METABOLISM AND INTERACTIONS OF PESTICIDES IN HUMAN AND ANIMAL IN VITRO

HEPATIC MODELS

Khaled M Abass

Profenofos, diuron and carbosulfan

• By CYP enzym menjadi metabolit lebih toksik/ karsinogenik.

Desthiopropylprofenofos,N-demethyldiuron,carbofuron

PERAN INDIVIDUAL ENZYM:

• CYP3A4 AND CYP2C19…profenofos and carbosulfan

• CYP1A2 AND CYP2C19….diuron