EFEK TOKSIK SUATU ZAT XENOBIOTIK Oleh Drs.Sudrajat,S.U. fmipa unmul Materi Kuliah FMIPA UNMUL Samarinda Tahun 2011

This is actually not a bad diagram, fairly logical.

Efek lokal Bioaktivasi Lebih toksik Efek lokal Bioaktivasi Pemapar Absorpsi Distribusi Biotransformasi Metabolit fisika Pernapas. antar sel fase 1 kimia Kulit sirkulasi fase 2 konsentr. Pencern. Bioinaktivasi Penyimpanan Efek Ekskresi Ekskresi

Exposure Site (skin, Gastro Intestinum, respiratory, placenta) D e L I V E R y Absorption Distribution Reabsorption Toxication Presystemic Elimination Distribution Away from Target Excretion Detoxication Ultimate Target Target molecule (protein, lipid, DNA, RNA)

Uptake Barriers Cell membrane Cell wall/cuticles/stomata Epithelial cells of GI tract Respiratory surface (lung, gill tracheae) Body surface

Gb. Beberapa membran yang harus dilewati oleh suatu senyawa xenobiotik

Foreign substances cross Filtration through pores Passive diffusion through membrane phospholipids Active transport Facilitated diffusion Phagocytosis Pinocytosis

BIOTRANSFORMASI Tujuan utama : detoksifikasi Lipofil hidrofil (polar) ekskresi Reaksi enzimatik : enzim, ko enzim Di semua sel, terutama sel hati Hasil : metabolit Bioaktivasi metabolit yang lebih aktif Bioinaktivasi metabolit kurang aktif Reaksi fase I : degradasi (oksidasi, reduksi, hidrolisis) Reaksi fase II : konjugasi polar

Oksidasi : Reaksi di mana substrat kehilangan elektron dalam reaksi : oksigenasi, dehidrogenasi atau transfer elektron Enzim : enzim oksidase (mis. Sitokrom) Mikrosomal atau non mikrosomal oksidasi seny. alifatik oksidasi seny. aromatik epoksidasi N-dealkilasi oksidasi amin desulfurisasi, dll

REDUKSI Reaksi kimia di mana substrat mendapat elektron Biasanya pada bahan yang memiliki atom oksigen sangat sedikit, misalnya golongan azo (N-N dengan ikatan rangkap) atau senyawa nitro (NO2), amino, dll. Amino metabolit aktif Karbon tetraklorida senyawa radikal

HIDROLISIS Terutama untuk golongan ester : asetilkolin (asetilkolin esterase) amida : amidase fosfat : fosfatase

KONJUGASI Oleh senyawa endogen konjugat Mekanisme ; 1. Glukoronid 2. Sulfat 3. Metilasi 4. Asetilasi 5. Glutation Hal ini akan menyebabkan terjadinya mekanisme kejenuhan

Sequestration Animals may store toxicants in inert tissues (e.g. bone, fat, hair, nail) to reduce toxicity Plants may store toxicants in bark, leaves, vacuoles for shedding later on Lipophilic toxicants (e.g. DDT, PCBs) may be stored in milk at high conc and pass to the young Metallothionein (MT) or phytochelatin may be used to bind metals

PENYIMPANAN Terutama bahan lipofilik dan yang tidak dibiotransformasi Tempat : jar. Lemak, tulang, hemoglobin, gusi, hati, ginjal, kuku, rambut, dll. Jar. Lemak : DDT hati-2 pada kondisi kelaparan atau trauma jaringan redistribusi efek toksik Penting dalam rantai trofik makanan kasus penyakit Minamata karena pajanan Merkuri organik Hati & ginjal : tempat penyimpanan sekaligus tempat biotransformasi

EKSKRESI Organ ekskretor utama : ginjal, saluran pencernaan, paru Lainnya : kulit, air susu, air mata Ginjal : organ utama, bahan hidrofil filtrasi glomeruli diffusi tubuler sekresi tubuler Paru : bahan-bahan volatil

Gb Skematik Mekanisme metabolik zat racun di luar hati dan di dalam hati

Gb Skematik Mekanisme metabolik zat racun di luar hati dan di dalam hati

FASE TOKS0DINAMIK

3). Fase Toksodinamik : Suatu kerja zat toksis pada umumnya adalah hasil interaksi dari sejumlah proses yang sangat rumit dan kompleks.

Induction of toxic effects Toxicodynamics Toxicodynamics (Determines the no. of receptors that can interact with toxicants) Binding Interaction Induction of toxic effects

Penyebaran bahan toksik dalam tubuh : Xenobiotik - sirkulasi sistemik --- Target Organ (Reseptor)

Gambar . Nasib zat kimia/xenobiotik di dalam tubuh

Mekanisme Efek Toksik Keberadaan xenobiotik dalam tubuh dapat menimbulkan efek toksik melalui dua cara, yakni berinteraksi secara langsung ( toksik intrasel) dan secara tidak langsung (toksik ekstrasel).

Gambar. Mekanisme Efek Toksik Intrasel Contoh: -Tetrasiklin -antikroba gol.sulfa -Radikal bebas -Insektisida pengikat enzim asetilkolinesterase - Ach menumpuk dalam sinapsis efek kolin berlebihan -Sianida -Botulisme Gambar. Mekanisme Efek Toksik Intrasel Toksisitas diawali dengan berinteraksinya secara langsung antara xenobitoik/zat kimia atau metabolitnya dengan reseptornya.

Gb. Mekanisme Toksik Ekstrasel Adanya senyawa kimia/xenobiotik dalam ekstraseluler dapat mengganggu aktivitas sel, mungkin menimbulkan perubahan struktur atau gangguan fungsi sel.

Reaction of the Ultimate toxicant with target molecule Noncovalent binding Reversible Hydrogen and ionic bonds Covalent binding Irreversible Permanently alters endogenous molecules Free radicals can bind covalently to molecules Hydrogen Abstraction Remove hydgogen and convert to double bonds Electron Transfer Exchange electrons to oxidize or reduce other molecules Enzymatic Reaction Affect normal reaction

MEKANISME KERJA POLUTAN THDP ORGAN TUBUH ORGANISME 1. Interaksi dengan sistem enzim : Inhibisi enzim tak bolak balik Inhibisi enzim secara reversible Pemutusan Reaksi Biokimia Sintesis Zat mematikan Pengambilan ion logam yang penting untuk kerja enzim Inhibisi penghantaran elektron dalam rantai respirasi

MEKANISME KERJA POLUTAN THDP BAGIAN TUBUH ORGANISME 2.Inhibisi pada transpor oksigen karena gangguan pada hemoglobin Keracunan karbon monoksida Pembentukan Metheglobin dan Sulfahemoglobin Proses Hemolitik

Pengaruh Penghantaran Rangsang Neurohumor 3.Interaksi dengan Fungsi Umum Sel Kerja Narkose Pengaruh Penghantaran Rangsang Neurohumor 4.Gangguan pada sintesis DNA dan RNA Kerja Sitostatika Kerja Imunsupresiva Kerja Mutagenik Kerja Karsinogenik

6.Reaksi Hipersensitif ( Reaksi alergi) Reaksi fotoalergik 5.Kerja Teratogenik 6.Reaksi Hipersensitif ( Reaksi alergi) Reaksi fotoalergik Sensibilisasi cahaya Reaksi fototoksis

8.Kerusakan kulit akibat zat kimia 9.Gas yang merangsang 7.Iritasi Kimia langsung pada Jaringan 8.Kerusakan kulit akibat zat kimia 9.Gas yang merangsang 10.Gas air mata 11.Zat yang berbau 12.Toksisitas pada Jaringan 13.Penimbunan (Sekuestrasi) Zat asing Penimbunan dalam jaringan lemak Penimbunan dalam Tulang Pneumokoniosis

Gb. Sifat-sifat fisika kimia dan struktur sebagai penentu tingkat toksisitas suatu xenobiotik

Wujud efek toksis dapat berupa : Perubahan biokimia Proses Fungsional Struktural sel/jaringan

Gambar. Sifat Efek Toksik

Cellular Dysfunction and Toxicities Gene expression Transcription DNA to RNA Signal Transduction Signals from cell surface receptors to control various cellular activities Cellular activity Influence excitable cells ( neurons, cardiac cells) Neurotransmitters Cell death Depletion of ATP Mitochondria

Apoptosis

Proliferation and Replacements Regeneration of Tissue Replacement of Lost Cells by Mitosis Cells adjacent to injury enter cell division Replacement of Extracellular Matrix Growth factors- proteins, collagens, etc. Inflammation Alteration of microcirculation and accumulation of inflammatory cells Produce reactive oxygen and nitrogen species

Carcinogensis Insufficient function of various repair mechanisms Failure of DNA repair Toxins may cause DNA adducts, strand breakage, oxidation Mutation of proto-oncogenes Proteins needed to control cell cycle Failure of apoptosis Promotion of mutation and continued growth of damaged cells Failure to terminate cell proliferation Tumor formation

Tissue Necrosis

Tissue Necrosis Cell death Injury overwhelms and disables repair mechanisms No repair of damaged molecules No elimination of damaged cells by apoptosis No replacement of lost cells by cell division

Fibrosis

Fibrosis A pathological condition that is characterized by excessive deposition of an extracellular matrix that is abnormal Increase in collagen, laminin, growth factors

Carcinogensis Insufficient function of various repair mechanisms Failure of DNA repair Toxins may cause DNA adducts, strand breakage, oxidation Mutation of proto-oncogenes Proteins needed to control cell cycle Failure of apoptosis Promotion of mutation and continued growth of damaged cells Failure to terminate cell proliferation Tumor formation

Sasaran Proses yang Terganggu Tabel 1. Rangkuman beberapa pengaruh biokimia dan fisiologis penting dari suatu zat beracun. No Sasaran Proses yang Terganggu 1. Membran sel Perubahan atau modifikasi permeabilitas memberan b. Pengacauan sistem transportasi membran sel 2. Enzim Inhibisi dapat balik atau tidak balik dari enzim (koenzim, subtrat atau pengaktif logam), oleh zat kimia 3. Metabolisme Lemak Pengacauan metabolisme lemak dapat menyebabkan kegagalan fungsi hati, termasuk akumulasi lemak patologis dalam hati dan kapasitas lemak untuk mengsintesis kolesterol dapat digagalkan.

Tabel 1. Rangkuman beberapa pengaruh biokimia dan fisiologis penting dari suatu zat beracun. No Sasaran Proses yang Terganggu 4. Biositensis Protein Sintesis zat protein dapat dipengaruhi oleh sejumlah besar zat eksogenus, terutama melalui penekanan kapasitas protein untuk mensintesis yang bertempat di dalam reticulkum kasar endoplasmik (r ER) di dalam sitoplasma. Dalam beberapa kasus, salah satu pengaruh dapat merangsang timbulnya pertambahan sintesis protein mikrosomal. 5. Sistem enzim Mikrosomal Pergantian dalam fungsi enzim mikrosomal-rangsangan atau inhibisi yang diinduksi oleh banyak zat kimia di lingkungan. 6. Proses Pengaturan dan Pertumbuhan Struktur atau kegiatan enzim pengatur dapat diubah dan sintesis, penyimpanan, pelepasan atau pengasingan hormon dapat digagalkan oleh zat beracun dalam berbagai cara, penurunan laju pertumbuhan dapat mengikuti gangguan kimiawi jalur dan laju metabolisme.

EFEK BIOLOGIS MERUPAKAN RESULTANTE AKHIR DARI SEJUMLAH PROSES YANG SANGAT KOMPLEKS, YAKNI INTERAKSI ANTARA FUNGSI HOMEOSTASISNYA DENGAN XENOBIOTIK. Jika proses homeostasis gagal, karena berbagai hal misalnya dosis terlalu tinggi, paparan konsentrasi terlalu pekat dan kontinyu, keadaan gizi kurang, dstnya maka akan terjadi efek biologis yang diekspresikan bermacam-macam .

Reversible – irreversible Segera – tertunda SPEKTRUM EFEK : Akut - kronik Lokal – sistemik Reversible – irreversible Segera – tertunda Perubahan morfologi-fungsi-biokimiawi

ORGAN TARGET DAN KERACUNANNYA: Hepatotoksik Nefrotoksik Neurotoksik Hematotoksik Pulmotoksik Dll.

Factors influencing toxicity : Form and innate chemical activity Dosage, especially dose-time relationship Exposure route Species Age Sex Ability to be absorbed Metabolisme Distribution within the body Excretion Presence of other chemicals

EFEK GENETIK RACUN Yakni dapat menyebabkan gangguan struktur dan jumlah kromosom a). Aneuploidisasi Susunan kromosom di dalam sel kelamin ( spermatozoa atau sel telur) tidak memisah. Sehingga jika terjadi fertilisasi, maka anak yang lahir memiliki susunan kromosom kurang atau lebih. Anak lahir cacat/ abnormal. b). Klastogenesis DNA rusak, misalnya akibat sinar ultraviolet atau bahan kimia. Anak lahir cacat/ abnormal. c). Mutagenesis Terjadi perubahan struktur gen, sehingga anak yang lahir akan cacat/ abnormal.

KARSINOGEN a). DNA REAKTIF KARSINOGEN Direct acting karsinogen Prokarsionogen Inorganik b). EPIGENETIK KARSINOGEN Promotor Cytotoxic Hormon Modifying Imunopressor Solid c). UNCLASSIFIED KARSINOGEN

DNA REAKTIF KARSINOGEN Direct acting karsinogen Bekerja langsung terhadap molekul-molekul nukleotida Tidak dijumpai di alam. Mis. Halogen ether, Nitrosoamida Prokarsinogen Reaksinya tidak langsung menyebabkan kanker Kanker muncul setelah terjadi aktivasi metabolis Dari alam atau sintetik. Mis. PAH, Aromatic Heterosiklik Amine, Senyawa azo, Senyawa N-Nitroso, Aldehyda, Hexamethylphosphoramida, Karbamat, Ethyonine, HC terhalogenisasi, mikroba karsinogenik, senyawa dari tumbuhan karsinogenik Inorganik Termasuk kelompok ini adalah Uranium, Polonium, Radium, Titanium, Nikel, kromium dan Cobalt Bersifat sinergestik dengan debu/ partikulat dan meningkatkan risiko kanker paru, saluran napas.

EPIGENETIK KARSINOGEN Kelompok ini tidak langsung hasil reaksi dengan materi genetik. a. Promotor Merupakan agen yang memberikan sarana pada dorman neoplastic untuk tumbuh menjadi tumor. Misalnya Tetradecanoyl Phorbol Acetate ( TPA), Phenolbarbital, Hydrocarbon terklorinasi, Saccharin, Butylated Hydroxyanisole dan Butylated Hydroxytoluol. b. Cytotoxic Merupakan penyebab kanker sebagai implikasi dari iritasi kronis, kemudian menjadi agen yang mengakibatkan sel menjadi degeratif sebagai konpensasi proliferasi yang menaikkan risiko kanker. Misalnya. Nitrolotriacetic Acid ( NTA)

c. Hormon Modifying Pada Usia di atas 40 tahun, hormon terumata estrogen dapat menyebabkan kanker. Misalnya. Estrogen, Androgen, 3-Aminotriazole, Ethylenethiourea Imunopressor Proses pemberian kekebalan kadang-kadang dapat menimbulkan kanker. Misalnya pemberian serum azathioprine pada hewan dapat menaikkan risiko leukemia dan pemberian obat 6-mercaptopurine dapat menaikkan risiko lymphoma. d. Solid Bahan padat dapat mendukung untuk proliferasi sel, sehingga menjadi kanker.Misalnya. Asbestos, Kompleks Iron-Carbohidrat

Lead

Lead Paint The use of lead in residential paint was banned in 1977 Lead-containing pigments still are used for outdoor paint products because of their bright colors and weather resistant properties Tetraethyl and tetramethyl lead are still used as additives in gasoline in several countries

Sources of Exposure Soil and dust Paint chips Contaminated water Parents lead-related occupation Folk remedies Congenital exposure Pica Developmental delay

Toxicocokinetics and Toxicoynamics Absorption: Lungs: depends on size particle GI: Adults: 20-30% Children: as much as 50% of dietary lead Inadequate intake of iron, calcium, and total calories are associated with higher lead levels Skin: Inorganic lead is not absorbed Organic lead is well absorbed Lead is carried bound to the RBC

Pharmacokinetics and Pharmacoynamics Distributed extensively throughout tissues: bone, teeth, liver, lung, kidney, brain, and spleen

Lead crosses the BBB and concentrates in the gray matter Body lead storage: bones- can constitute a source of remobilization and continued toxicity after the exposure has ceased Lead crosses the BBB and concentrates in the gray matter Lead crosses the placenta Excretion: Kidneys. The excretion increases with increasing body stores (30g-200 g/day) Feces

Clinical Manifestation Acute toxicity Acute encephalopathy, renal failure and severe GI symptoms

Chronic and Long Term Toxicity- Pathophysiology Lead has affinity for SH groups and is toxic to zinc-dependent enzyme systems Heme synthesis: hemoglobin, cytochromes Steroid metabolism and membrane integrity Interference in vitamin D synthesis in renal tubular cells (conversion of 1-hydroxyvitamin D to 1,25-hydroxyvitamin D)

Mitochondrion Copro* Uropor PBG ALA* Copro-0 Copro Protoporphyrin IX* Heme Cytoch-C Bilirubin + Fe ALA-D Pb Ferro-C 4Fe++ ALA-S Oxidase (microsomal) Glycine Succinyl-Coa ALA- aminolevulinic acid  in plasma and urine COPRO- coprorphyrinogen  in urine Protoporphyrin  accumulates in the RBC

General Signs and Symptoms of Lead Toxicity Fatigue Irritability Lethargy Paresthesis Myalgias Abdominal pain Tremor Headache Vomiting Weight loss Constipation Loss of libido Motor neuropathy Encephalopathy Cerebral edema Seizures Coma Severe abdominal cramping Epiphyseal lead lines in children (growth arrest) Renal failure

Range of Lead-induced Health Effects in Adults and Children Blood lead levels Adults Children 10 g/dL Hypertension may occur Crosses placenta Impairment IQ, growth Partial inhibition of heme synthesis 20 g/dL Inhibition of heme synthesis Increased erythrocyte protoporphyrin Beginning impairment of nerve conduction velocity 30 g/dL Systolic hypertension Impaired hearing() Impaired vitamin D metabolism 40 g/dL Infertility in males Renal effects Neuropathy Fatigue, headache, abd pain Hemoglobin synthesis inhibition 50 g/dL Anemia, GI sx, headache, tremor Colicky abd pain, neuropathy 100 g/dL Lethargy, seizures, encephalopathy Encephalopathy, anemia, nephropathy, seizures

Childhood Lead Poisoning Childhood lead poisoning is now defined as a blood lead level of 10 g/dl

The average lead level of American children is 2 g/dl 8.9% of American children have lead poisoning Lead intoxication is more prevalent in minority groups and among those living in the northeast

Neurotoxicity of Lead in Childhood Mental retardation in severe lead intoxication  5 points in IQ for every 10 g/dl  in blood lead level- population based studies Other adverse developmental outcomes: Aggression Hyperactivity Antisocial behaviors Learning disability- impairment in memory, auditory processing, and visual-motor integration. The IQ is normal. These effects has been demonstrated with blood lead levels as low as 6 g/dl

Arsenic

Introduction Arsenic is common in the environment Sources Groundwater Arsenic containing mineral ores Industrial processes Semiconductor manufacturing (gallium arsenide) Fossil fuels Wood treated with arsenic preservatives Metallurgy Smelting (copper, zinc, lead) and refining of metals and ores Glass manufacturing

Introduction Commercial products Food Others Wood preservatives Pesticides Herbicides Fungicides Food Seafood and fish Others Antiparasitic drugs Folk remedies

Soil Pica Soil pica behavior: when children ingest large amounts of soil at a time (e.g. up to 1 teaspoon or 5,000mg) Children 1 to 2 years old have strongest soil pica behavior, which may occur as part of their normal exploratory behavior Preschool children also purposely eat soil for unknown reasons Some cultures promote eating soil, specifically clay, as part of a cultural practice

Toxicokinetics T1/2 of inorganic arsenic in the blood is 10 hrs and of organic arsenic is around 30 hours 2-4 weeks after the exposure ceases, most of the remaining arsenic in the body is found in keratin-rich tissues (nails, hair, skin)

Toxicokinetics Inorganic arsenic is converted to organic arsenic (biomethylation to monomethyl arsonic- MMA or DMA) in the liver. This may represent a process of detoxification Renally excreted (30-50% of inorganic arsenic is excreted in about 3 days). Both forms are excreted depend on the acuteness of the exposure and dose

Pathophysiology Trivalent forms: Pentavalent forms bind to sulfhydryl groups leading to inhibition of enzymatic systems inhibit the Krebs cycle and oxidative phosporylation. These lead to inhibition of ATP production Pentavalent forms can replace the stable phosphate ester bond in ATP and produce an arsenic ester stable bond which is not a high energy bond Endothelial damage, loss of capillary integrity, capillary leakage, volume loss, shock

Manifestations of acute arsenic poisoning Bodily system affected Symptoms or signs Time of onset Systemic Thirst Hypovolemia, Hypotension Minutes Minutes to hours Gastrointestinal Garlic or metallic taste Burning mucosa Nausea and vomiting Diarrhea Abdominal pain Hematemesis Hematochezia, melena Rice-water stools Immediate Hours Hematopoietic system Hemolysis Hematuria Lymphopenia Pancytopenia Several weeks Pulmonary (primarily in inhalational exposures) Cough Dyspnea Chest Pain Pulmonary edema Liver Jaundice Fatty degeneration Central necrosis Days Kidneys Proteinuria Acute renal failure Hours to days

Palmer Keratosis

Mercury

Mercury Occurs in three forms (elemental, inorganic salts, and organic compounds) Contamination results from mining, smelting, and industrial discharges. Mercury in water can be converted by bacteria to organic mercury (more toxic) in fish. Can also be found in thermometers, dental amalgams, fluorescent light bulbs, disc batteries, electrical switches, folk remedies, chemistry sets and vaccines.

Mercury - Exposure Elemental liquid at room temperature that volatizes readily rapid distribution in body by vapor, poor in GI tract Inorganic poorly absorbed in GI tract, but can be caustic dermal exposure has resulted in toxicity Organic lipid soluble and well absorbed via GI, lungs and skin can cross placenta and into breast milk

Elemental Mercury At high concentrations, vapor inhalation produces acute necrotizing bronchitis, pneumonitis, and death. Long term exposure affects CNS. Early: insomnia, forgetfulness, anorexia, mild tremor Late: progressive tremor and erethism (red palms, emotional lability, and memory impairment) Salivation, excessive sweating, renal toxicity (proteinuria, or nephrotic syndrome) Dental amalgams do not pose a health risk.

Inorganic Mercury Gastrointestinal ulceration or perforation and hemorrhage are rapidly produced, followed by circulatory collapse. Breakdown of mucosal barriers leads to increased absorption and distribution to kidneys (proximal tubular necrosis and anuria). Acrodynia (Pink disease) usually from dermal exposure maculopapular rash, swollen and painful extremities, peripheral neuropathy, hypertension, and renal tubular dysfunction.

Organic Mercury Toxicity occurs with long term exposure and effects the CNS. Signs progress from paresthesias to ataxia, followed by generalized weakness, visual and hearing impairment, tremor and muscle spasticity, and then coma and death. Teratogen with large chronic exposure Asymptomatic mothers with severely affected infants Infants appeared normal at birth, but psychomotor retardation, blindness, deafness, and seizures developed over time.