Digestion
Route of Inhalation
METABOLISME
Entry Transdermal
Intra Venous
METILASI
RH + O2 ROH + H2O
Cyt P450 tereduksi Cyt P450 teroksidasi
SIFAT Cyt P450:
Suatu Hemoprotein (mirip hemoglobin)
Memiliki isoform yang banyak (kurang lebih 150)
numenklatur sistematik
Memiliki spesifitas substrat yang luas
Terdapat pada banyak spesies, termasuk bakteri
Terdapat dalam membran Retikulum Endoplasma Hati
Produk dapat bersifat Mutagenik/Karsinogenik
Dapat dirangsang Interaksi Obat
CYP2C9 berperan pada metabolisme Warfarin (antikoagulan)
Produksi CYP2C9 dapat ditingkatkan oleh Phenobarbital
SIFAT Cyt P450:
Konsumsi ethanol CYP2E1 k komponen asap rokok & beberapa
macam pelarut karsinogenik
CYP1A1 berperan pada metabolisme PAH (Polycyclic Aromatic
Hydrocarbons) yg merupakan suatu karsinogen
CYP1A1 = (aromatic hydrocarbon hydroxylase = AHH)
Rokok : reaksi hidroksilasi PAH menjadi aktif Ca Paru
plasenta: PAH meningkat
Polimorfisme metabolisme obat i
CYP2D6 menurunkan metabolisme debrisoquin (obat antihipertensi)
dan sparteine (antiaritmia & oksitosik)
CYP2A6: nikotin konitin. Menghambat enzim ini dapat menolong
perokok.
Some properties of human cytochrome P450s.
Involved in phase I of the metabolism of innumerable xenobiotics, including perhaps 50% of the
drugs administered to humans
Involved in the metabolism of many endogenous compounds (eg, steroids)
All are hemoproteins
Often exhibit broad substrate specificity, thus acting on many compounds; consequently, different
P450s may catalyze formation of the same product
Extremely versatile catalysts, perhaps catalyzing about 60 types of reactions
However, basically they catalyze reactions involving introduction of one atom of oxygen into the
substrate and one into water
Their hydroxylated products are more water-soluble than their generally lipophilic substrates,
facilitating excretion
Liver contains highest amounts, but found in most if not all tissues, including small intestine, brain,
and lung
Located in the smooth endoplasmic reticulum or in mitochondria (steroidogenic hormones)
In some cases, their products are mutagenic or carcinogenic
Many have a molecular mass of about 55 kDa
Many are inducible, resulting in one cause of drug interactions
Many are inhibited by various drugs or their metabolic products, providing another cause of drug
interactions
Some exhibit genetic polymorphisms, which can result in atypical drug metabolism
Their activities may be altered in diseased tissues (eg, cirrhosis), affecting drug metabolism
Genotyping the P450 profile of patients (eg, to detect polymorphisms) may in the future permit
individualization of drug therapy
Substrat-substrat Sitokrom P450
CYP2D6 Substrates
Antiarrhythmics: Flecainide, Mexiletine, Propafenone
Antidepressants: Amitriptyline, Paroxetine, Venlafaxine, Fluoxetine
(Prozac), Trazadone
Antipsychotics: Clorpromazine, Haloperidol, Thoridazine
Beta-Blockers: Labetalol, Timolol, Propanolol, Pindolol, Metoprolol
Analgesics: Codeine, Fentanyl, Meperidine, Oxycodone, Propoxyphene
CYP3A4 Substrates
Acetominophen (Tylenol)
Codeine (narcotic)
Cyclosporin A (an immunosuppresant),
Diazepam (Valium)
Erythromycin (antibiotic)
Lidocaine (anaesthetic),
Lovastatin (HMGCoA reductase inhibitor, a cholesterol lowering drug),
Taxol (cancer drug),
Warfarin (anticoagulant).
Humans have 18 families of cytochrome P450 genes and 43 subfamilies (Nelson, 2003):
CYP1 drug metabolism (3 subfamilies, 3 genes, 1 pseudogene) CYP1A2
CYP2 drug and steroid metabolism (13 subfamilies, 16 genes, 16 pseudogenes) CYP2A6,
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1
CYP3 drug metabolism (1 subfamily, 4 genes, 2 pseudogenes) CYP3A4
CYP4 arachidonic acid or fatty acid metabolism (5 subfamilies, 11 genes, 10 pseudogenes)
CYP5 thromboxane A2 synthase (1 subfamily, 1 gene)
CYP7A bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus (1 subfamily member)
CYP7B brain specific form of 7-alpha hydroxylase (1 subfamily member)
CYP8A prostacyclin synthase (1 subfamily member)
CYP8B bile acid biosynthesis (1 subfamily member)
CYP11 steroid biosynthesis (2 subfamilies, 3 genes)
CYP17 steroid biosynthesis (1 subfamily, 1 gene) 17-alpha hydroxylase
CYP19 steroid biosynthesis (1 subfamily, 1 gene) aromatase forms estrogen
CYP20 unknown function (1 subfamily, 1 gene)
CYP21 steroid biosynthesis (1 subfamily, 1 gene, 1 pseudogene)
CYP24 vitamin D degradation (1 subfamily, 1 gene)
CYP26A retinoic acid hydroxylase important in development (1 subfamily member)
CYP26B probable retinoic acid hydroxylase (1 subfamily member)
CYP26C probabvle retinoic acid hydroxylase (1 subfamily member)
CYP27A bile acid biosynthesis (1 subfamily member)
CYP27B vitamin D3 1-alpha hydroxylase activates vitamin D3 (1 subfamily member)
CYP27C unknown function (1 subfamily member)
CYP39 7-alpha hydroxylation of 24-hydroxycholesterol (1 subfamily member)
CYP46 cholesterol 24-hydroxylase (1 subfamily member)
CYP51 cholesterol biosynthesis (1 subfamily, 1 gene, 3 pseudogenes) lanosterol 14-alpha
demethylase
Metabolisme Xenobiotik: Fase II: KONJUGASI
A. GLUKURONIDASI
Proses sama dengan glukuronidasi Bilirubin
UDP-Asam Glukuronat Glukuronil
Glukuronil Transferase
YANG DIIKAT
2 Asetilimunofluoren
Anilin
Asam Benzoat
Meprobamat
Phenol
Steroid
B. SULFASI
Donor Sulfat: 3 Phosfat 5 Phosfosulfat (PAPS)
Yang diikat: Alkohol, Fenol, Arilamina
Pentose
FAD Glutation Se Glutation
Phosphat
Reduktase Peroksidase
Pathway
E. METILASI
H2O Pi + PPi Donor metil
Farmakologik
Toksik
Imunologik
Karsinogenik
RESPON TERHADAP XENOBIOTIK
Obat: fase 1 akan mengubah obat menjadi bentuk aktif, atau dapat
menurunkan/menghilangkan khasiat akibat perbedaan genetik
antar individu FARMAKOGENETIK (mempelajari pengaruh faktor
genetik terhadap variasi respon obat dan toksisitas)
GSH S-Transferase
SITOKROM
Epoksida Hidrolase
P450
Xenobiotik Metabolit Reaktif Metabolit Non Toksik
Kerusakan Sel
Pengikatan Kovalen dg Makromolekul Sel Merusak DNA,
RNA dan Protein (cytotoxicity)
Hapten merangsang produksi Antibodi Kerusakan sel akibat
mekanisme imunologi
Reaksi antara spesies Karsinogen kimiawi yg aktif dg DNA
Kanker
Benzo[a]piren memerlukan aktifasi Monooksigenase Karsi-
nogenik (tdk langsung)
Senyawa yg mengalami Alkilasi langsung bereaksi dg DNA
(Karsinogenik langsung)
Monooksigenase
Substrat Prokarsinogen Senyawa Epoksida
Epoksida + H2O Dihidrodiol (tdk reaktif)
Epoksida Hidrolase
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