ERWIN DYAH N
DEFINISI
Biotransformasi = proses perubahan bahan kimia menjadi bahan kimia lain melalui reaksi kimia yg terjadi di dalam tubuh Proses biotransformasi = Metabolisme / transformasi metabolik Namun, pd metabolisme kadang tdk spesifik hanya proses transformasi saja, di sini juga terjadi fase toksikokinetik
Biotransformasi
Penting untuk kehidupan karena : - ada proses perubahan zat gizi (nutrien) bahan yg diperlukan untuk fungsi tbh secara normal Ex: Pd obat -- kdg yg dibutuhkan metabolitnya-bukan obat aslinya Misal: phenoxybenzamine (Dibenzyline)- obat HT hrs ditransformasi menjadi metabolitnya ( bahan aktif yg diperlukan adlh metabolitnya)
Toksikan yg lipofilik , non polar, BM rendah mdh menembus membran (kulit, GIT, & paru) Lipofilik sulit dieliminasi akumulasi level bahaya Lipofilik sebag. > dpt diubah metabolit yg hidrofilik > sulit menembus membran sel penting & > mdh dikeluarkan Jadi biotransformasi mrpk kunci utama mekanisme pertahanan tubuh!
Tbh manusia punyaikapasitas biotransformasi yg sangat baik u/ sebag. > xenobiotik & limbah tubuh Limbah metabolisme yg harus dieliminasi misalnya: Hb penghancuran SDM pelepasan Hb Pd kondisi normal : Hb biotransformasi Bilirubin (toksik bagi otak bayi baru lahir pd kadar tinggi irreversible brain injury) Bilirubin (lipofilik) biotransformasi hidrofilik ekskresi (urin & feces)
Kadang, biotransformasi dpt menghasilkan metabolit yg dpt berinteraksi dg DNA efek parah pd kesh. Ex: Vinyl chloride vinyl chloride epoxide berikatan kovalen dg . DNA & RNA Cancer liver.
For Academics :
The term "biotransformation" refers to: a. an increase in electrical charge in tissues produced by a biological transformer b. chemical reactions in the body that create a new chemical from another chemical c. the transformation of one type of cell in a tissue to another type of cell
Biotransformation is the process whereby a substance is changed from one chemical to another (transformed) by a chemical reaction within the body.
For Academics :
Detoxification is a biotransformation process in which: a. metabolites of lower toxicity are produced b. metabolites of higher toxicity are produced
When biotransformation results in metabolites of lower toxicity, the process is known as detoxification.
Chemical reactions
Terjadi terus menerus di tubuh terjadi Mrpk aspek kehidupan normal berperan dlm : a. Membangun jaringan baru b. Pembongkaran jaringan yg sdh tua c. Mengubah makanan energi d. Pembuangan zat sisa e. Eliminasi xenobiotic toksik Di dlm tbh >> reaksi kimia sangat teratur & terjadi saat dibutuhkan >> terjadi pd kecepatan yg cukup- krn peran enzym sbg katalis Katalis : bahan kimia yg membantu mempercepat reaksi ttp tidak ikut bereaksi
Enzym
Mrpk katalis untuk hampir semua reaksi kimia dlm tbh Tanpa enzym reaksi lambat masalah kesehatan Ex: Org yg mengalami phenylketonuria (PKU) tak bs menggunakan pemanis yg mengandung aspartame (in Equal). Aspartame = phenylalanine ( ada dlm sebagian besar makanan yg mengd prot.) ggn genetik PKU tdk dpt mengubah : phenylalanine tyrosine (another amino acid) menumpuk dlm tbh Retardasi mental parah Bayi : hrs rutin dicek PKU (saat lahir) jk + diet khusus (dibatasi asupan phenylalanine saat bayi/anak2)
Reaksi enzymatik
tdk selalu sederhana Ada enzym yg bth cofactors / co-enzymes u/ membantu tugasnya sbg katalis co-factors : komponen normal di sebagian besar sel & sering terlibat dlm reaksi perubahan zat gizi menjadi energi Contoh co-factor : Vitamin Yg memegang kunci transformasi xenobiotik adalah OBAT atau enzym
The relationship of substrate, enzyme, co-enzyme, and transformed product is illustrated below:
Specifisitas Enzym
contoh
Absolut Spesificity: Formaldehyde dehydrogenase hanya sbg katalisator pd reaksi kimia formaldehyde Acetylcholinesterase hanya sbg katalisator bahan kimia neurotransmiter acetylcholine Group specivicity: Alcohol dehydrogenase mempunyai group specificity krn dpt mengubah beberapa jenis alkohol termasuk methanol & ethanol Linkage specivicity: N-oxidation dpt mengkatalis reaksi yg ada ikatan nitrogen dg menggantikan gugus nitrogen dg oksigen
Penamaan enzym
Kecuali untuk pepsin & trypsin semua diberi akhiran ase + bahan yg bereaksi dan tipe reaksi Ex: Alcohol dehydrogenase = enzym yg mengubah Alkohol dengan melepaskan hidrogen hasilnya aldehyde atau keton
ADH = alcohol dehydrogenase, a specific catalyzing enzyme NAD = nicotinamide adenine dinucleotide, a common cellular reducing agent
Jika dosis ber >> < enzym obat mengalami reaksi melalui jalur lain bioaktivasi hepatotoksik O.k.i hanya boleh diminum setiap 4-6 jam dan tidak boleh diminum me>i 4 dosis/24 jam Enzym jumlah terbatas dapat kehabisan (melebihi kemampuan tubuh untuk mensintesis kembali) "Dose Makes the Poison."
Bahan yg tdk perlu melalui fase I jadi langsung ke fase II Ex: Phenol Phenol langsung terkonjugasi menjadi metabolit yg bs langsung di ekskresi Benzen perlu fase I & II Pada fase I : benzen phenol Pada fase II : phenol terkonjugasi phenyl sulfate
Biotransformasi benzen
Fase I : a. Oksidasi
Proses dmn molekul/Substrat kehilangan elektron reaksi = oksidasi krn pertamakali ditemukan mrpk reaksi penambahan oksigen Reaksi oksidasi tdk selalu melibatkan Oksigen Contoh reaksi oksidasi yg tak melibatkan oksigen : - dehydrogenation lepasnya ion H molekul - electron transfer berpindahnya elektron dari substrat
Fase I : b. Reduksi
Substrat menerima elektron Paling banyak terjadi pd xenobiotik jika O2 rendah Reduksi dpt terjadi pada ikatan ganda nitrogennitrogen (azo reduction) atau pada kelompok nitro (NO2). Seringkali, AA yg dihasilkan akan teroksidasi membentuk metabolit yg toksik Beberapa bahan kimia spt CCl4 dapat tereduksi oleh radikal bebas yg sangat reaktif thd jaringan Jadi : Reduksi > sering mengakibatkan Bioaktivasi
Fase I : Hydrolisis
Penambahan air menyebabkan toksikan terpecah menjadi 2 fragmen atau molekul yg > kecil --Kelompok hidroksil(OH-) & atom hidrogen Yg sering mengalami hidrolisis : esters, amines, hydrazines, & carbamates Contoh biotransformasi procaine (local anesthetic) yg terhidrolisis menjadi 2 bhn kimia lain sbb :
Hidrolisis
Fase II
xenobiotic yg telah melewati fase I new intermediate metabolite yang terdiri atas bahan kimia reaktif spt: hydroxyl (-OH), amino (-NH2), &carboxyl (COOH) Bebrapa blm menjadi ckp hidrofilik msh sulit dikeluarkan harus melalui fase II (reaksi biotransformasi tambahan)
Fase II
Reaksi konjugasi Molekul normalnya dlm tubuh ditambahahkan pd metabolit dari reaksi fase I terkonjugasi (> hidrofilik) mdh dikeluarkan Reaksi utama pada fase II:
glucuronide conjugation - most important reaction sulfate conjugation - important reaction acetylation amino acid conjugation glutathione conjugation methylation
For Academics :
The substances in the body that accelerate chemical reactions are known as: a. amino acids b. substrates c. enzymes
Enzymes are proteins that catalyze nearly all biochemical reactions in the body.
For Academics :
The convention used to name specific enzymes consists of : a. combining the substrate name with the type of chemical reaction b. combining the target organ and the type of chemical reaction c. combining the substrate name with the form of toxicity
Enzyme names end in "ase" and usually combine the substrate acted on and the type of reaction catalyzed (a)
For Academics :
Biotransformation reactions are classified as Phase I and Phase II. The basic difference is: a. Phase I reactions conjugate a substrate whereas Phase II reactions oxidize the substance b. Phase I reactions generally add a functional structure whereas Phase II reactions conjugate the substance c. a Phase I reaction generally makes a substance more hydrophilic than a Phase II reaction
Phase I reactions are generally reactions which modify the chemical by adding a functional structure. This allows the substance to "fit" into the Phase II enzyme so that it can become conjugated (joined together) with another substance. Phase II reactions consist of those enzymatic reactions that conjugate the modified xenobiotic with another substance (b)
For Academics :
The difference between oxidation and reduction reactions is: a. a substrate gains electrons from an oxidation reaction whereas it loses electrons by a reduction reaction b. oxygen is removed from a substrate in oxidation and added in the reduction reaction c. a substrate losses electrons from an oxidation reaction whereas it gains electrons by a reduction reaction
Oxidation is a chemical reaction in which a substrate loses electrons. Reduction is a chemical reaction in which the substrate gains electrons (c)
For Academics :
Which conjugation reaction is the most common in the biotransformation of xenobiotics? a. amino acid conjugation b. glucuronide conjugation c. methylation
Glucuronide conjugation is one of the most important and common Phase II reactions. Glucuronidation is a high-capacity pathway for xenobiotic conjugation (b)
Biotransformation Sites
Enzym Biotransformasi tersebar luas di seluruh tubuh Liver organ biotransformasi utama - besar - banyak enzym di sini Ginjal & paru kapasitas biotransformasi 10-30% dibanding liver Kulit , usus, testis, plasenta kapasitas rendah O.k.i liver sangat rentan thd toksisitas xenobiotic yang mengalami bioaktivasi
Enzym dlm sel berada pd : microsomes (small vesicles) dari Endoplasmic reticulum dan bagian sitoplasma (cytosol) Aktifitas transformasi sebagian kecil terjadi juga di : mitochondria, nucleus, dan lysosome
Cytochrome P-450
Enzym utama pd Fase I sistem enzym ini disebut : "mixed function oxidase (MFO) " system. Ada di microsome Bertanggungjawab pada reaksi oksidasi
Liver
Biotransformasi hampir semua xenobiotics Aliran darah dari GIT langsung ke liver liver rentan thd toksikan yg melalui ingesti Darah dari GIT tdk langsung ke sirkulasi umum (lewat EHC) disebut "first pass" phenomena. Dari liver darah ke seluruh area tbh (sebag besar sdh didetoks di liver) Metabolit yg toksik ada pd kadar tinggi di liver
For Academics :
The organ that has the greatest ability to biotransform xenobiotics is the: a. liver b. pancreas c. skin
Biotransforming enzymes are widely distributed throughout the body. However, the liver has the largest concentration of all organs and thus has a very high capacity for biotransformation.
For Academics :
The "first pass" phenomenon pertains to: a. the situation where xenobiotics that are absorbed from the GI tract first enter the circulating blood before going to the liver b. a condition where the liver first biotransforms a xenobiotic by Phase II reaction before it is biotransformed by a Phase I reaction c. an anatomical arrangement in which xenobiotics absorbed from the intestine go to the liver first rather than into the systemic circulation
Blood leaving the gastrointestinal tract does not directly flow into the general circulatory system. Instead, it flows into the liver first via the portal vein. This is known as the "first pass" phenomena.(c)
genetik
Ada yg secara genetik dpt bereaksi cepat pd acetylasi
Enzyme Inhibition
Bs o.k. Pajanan xenobiotics Ok pajanan xenobiotik ttt menghambat kapasitas biotransformasi (o.k. Hambatan pd enzym ttt) Mekanisme utama : kompetisi antara 2 zat thd enzym oksidasi atau konjugasi Zat 1 menggunakan enzym yg dibutuhkan untuk memetabolisme zat 2
Enzyme Induction
Adanya pajanan dengan bhn kimia ttt / obat meningkatkan kapasitas biotransformasi xenobiotik Zat 1 merangsang tbh untuk produksi enzym aktifitas enzym meningkat biotransformasi meningkat Contoh penginduksi : Alcohol, isoniazid, polycyclic halogenated aromatic hydrocarbons (e.g., dioxin), phenobarbital, and cigarette smoke. Reaksi yg paling sering terinduksi : reaksi yg melibatkan enzym cytochrome P-450
For academics
Selective toxicity refers to a difference in the toxicity of a xenobiotic to different species. This selective toxicity can usually be attributed to: a. differences in the ability to absorb the xenobiotic b. differences in organ systems between species c. differences in capability to biotransform the xenobiotic
A difference between species in their capability to biotransform a specific chemical is normally the basis for a chemical's selective toxicity.