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slide kuliah fakultas kedokteran xenobiotic
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7/18/2019 Xeno Biotic
http://slidepdf.com/reader/full/xeno-biotic-56d46bbf765e0 1/14
7/18/2019 Xeno Biotic
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Metabolisme Xenobiotik
Senyawa asing yg masuk kedalam tubuh (obat, zat
aditif, polutan, dll.)
DigestionRoute of Inhalation
Entry Transdermal
Intra Venous
etabolisme ! " #ase FASE I
FASE II
METABOLISME
7/18/2019 Xeno Biotic
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Metabolisme Xenobiotik: Fase I Deaminasi
HIDROKSILASI Dehalogenasi
onooksigenase Desulfurasi
Sitokrom $%&' poksidasi
$eroksigenasi
eduksi
ESTERASI
7/18/2019 Xeno Biotic
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Metabolisme Xenobiotik: Fase II Asam Glukoronat
Sulfat
Asetat
Glutation
TUJUAN eningkatkan *elarutan+$olaritas EKSKRESI
KONJUGASI
METILASI
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Metabolisme Xenobiotik: Fase I: HIDROKSILASI
R - " - /0D$ - - R1 - " - /0D$
Cyt P450 tereduksi Cyt P450 teroksidasi
SIFAT Cyt P450: Suatu emoprotein
2erfungsi pada metabolisme 3enobiotik dan Steroid
Spesifikasi substrat sangat luas
Terdapat dalam etikulum ndoplasma ati
$roduk dapat bersifat utagenik+*arsinogenik
Dapat dirangsang Interaksi bat
45$"46 berperan pada metabolisme 7arfarin (antikoagulan)
$roduksi 45$"46 dapat ditingkatkan oleh $henobarbital
*onsumsi ethanol 45$"8 komponen asap rokok 9 beberapa
ma:am pelarut
karsinogenik $olimorfisme metabolisme obat
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Substrat;substrat Sitokrom $%&'
CYP2D6 Subt!"t#
0ntiarrhythmi:s! #le:ainide, e<iletine, $ropafenone
0ntidepressants! 0mitriptyline, $aro<etine, Venlafa<ine, #luo<etine($roza:), Trazadone
0ntipsy:hoti:s! 4lorpromazine, aloperidol, Thoridazine
2eta;2lo:kers! =abetalol, Timolol, $ropanolol, $indolol, etoprolol
0nalgesi:s! 4odeine, #entanyl, eperidine, <y:odone, $ropo<yphene
CYP$A4 Subt!"t#
0:etominophen (Tylenol)
4odeine (nar:oti:)
4y:losporin 0 (an immunosuppresant),
Diazepam (Valium)
rythromy:in (antibioti:)
=ido:aine (anaestheti:),
=o>astatin (?4o0 redu:tase inhibitor, a :holesterol lowering drug),
Ta<ol (:an:er drug),
7arfarin (anti:oagulant).
7/18/2019 Xeno Biotic
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Hu%"& '"(# )* +"%,-,# .+ /yt./'!.%# P450 #&# "&1 4$ ub+"%,-,# N#-.&3 200$:
45$8 drug metabolism (@ subfamilies, @ genes, 8 pseudogene) A 45$80"
45$" drug and steroid metabolism (8@ subfamilies, 8B genes, 8B pseudogenes) A 45$"0B,
45$"2B, 45$"4C, 45$"46, 45$"486, 45$"DB, 45$"8
45$@ drug metabolism (8 subfamily, % genes, " pseudogenes) A 45$@0%
45$% ara:hidoni: a:id or fatty a:id metabolism (& subfamilies, 88 genes, 8' pseudogenes)
45$& thrombo<ane 0" synthase (8 subfamily, 8 gene)45$0 bile a:id biosynthesis ;alpha hydro<ylase of steroid nu:leus (8 subfamily member)
45$2 brain spe:ifi: form of ;alpha hydro<ylase (8 subfamily member)
45$C0 prosta:y:lin synthase (8 subfamily member)
45$C2 bile a:id biosynthesis (8 subfamily member)
45$88 steroid biosynthesis (" subfamilies, @ genes)
45$8 steroid biosynthesis (8 subfamily, 8 gene) 8;alpha hydro<ylase45$86 steroid biosynthesis (8 subfamily, 8 gene) aromatase forms estrogen
45$"' unknown fun:tion (8 subfamily, 8 gene)
45$"8 steroid biosynthesis (8 subfamily, 8 gene, 8 pseudogene)
45$"% >itamin D degradation (8 subfamily, 8 gene)
45$"B0 retinoi: a:id hydro<ylase important in de>elopment (8 subfamily member)
45$"B2 probable retinoi: a:id hydro<ylase (8 subfamily member)
45$"B4 probab>le retinoi: a:id hydro<ylase (8 subfamily member)45$"0 bile a:id biosynthesis (8 subfamily member)
45$"2 >itamin D@ 8;alpha hydro<ylase a:ti>ates >itamin D@ (8 subfamily member)
45$"4 unknown fun:tion (8 subfamily member)
45$@6 ;alpha hydro<ylation of "%;hydro<y:holesterol (8 subfamily member)
45$%B :holesterol "%;hydro<ylase (8 subfamily member)
45$&8 :holesterol biosynthesis (8 subfamily, 8 gene, @ pseudogenes) lanosterol 8%;alpha
demethylase
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Metabolisme Xenobiotik: Fase II: KONJUGASIA GLUKORONIDASI
$roses sama dengan glukuronidasi 2ilirubin
ED$;0sam ?lukuronat ?lukuronil
Glukuronil Transferase
YANG DIIKAT
" A 0setilimunofluoren
0nilin
0sam 2enzoat
eprobamat
$henol
Steroid
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SULFASI Donor Sulfat! @F A $hosfat A &F A $hosfosulfat ($0$S)
5ang diikat! 0lkohol, #enol, 0rilamina
4. */GE?0SI D/?0/ ?=ET0TI/
?lutation H γ ;?lutamil Sisteinil ?lisin H ?S
- ?S 1S1? (Dalam =i>er)
?lutation S;Transferase
0setil;*o0 *o0
1S1? S1? - 0s. erkapturat1
Erine
7/18/2019 Xeno Biotic
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FUNGSI GLUTATION
8. $enguraian "" (nzim! ?lutation $eroksidase)
/0D$ - - ?1S1S1? "o
#0D Se
" /0D$ "?1S ""
". $ereduksi penting intraseluler mempertahankan gugus S
essensial untuk enzim yang tereduksi. 4ontoh! Defisiensi enzim ?;B;$D 0nemia emolitik
@. engangkut asam amino melewati membran sel dalam ginal
0sam 0mino - ?S γ ;?lutamil;0sam 0mino - Sisteinil?lisin
γ -Glutamil Transferase (γ ;?T)
$entose
$hosphat
$athway
?lutation
eduktase?lutation
$eroksidase
7/18/2019 Xeno Biotic
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D. 0STI=0SI
3 - 0setil;*o0 0setil A 3 - *o0
Asetil Transferase
Sifat $olimorfisme enzim T*SI* (4ontoh! I/)
. TI=0SI" $i - $$i
=; etionin - 0T$ S A 0denosil A = A etionin (etionin aktif)
3 - etil 3 A etil nzim! etil Transferase
Donor metil
7/18/2019 Xeno Biotic
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S$/ T0D0$ 3/2ITI*etabolisme 3enobiotik JDetoksifikasiK
JToksikK
SIT*
$%&'
?S S;Transferase
poksida idrolase
3enobiotik etabolit eaktif etabolit /on Toksik
Ikatan *o>alen terhadap akromolekul
*erusakan Sel apten
$roduksi 0ntibodi
*erusakan Sel
utasi
*anker
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$engikatan *o>alen dg akromolekul Sel erusak D/0,
/0 dan $rotein
apten merangsang produksi 0ntibodi *erusakan sel akibat
mekanisme imunologi
eaksi antara spesies *arsinogen kimiawi yg aktif dg D/0 *anker
2enzoLαMpiren memerlukan aktifasi onooksigenase *arsi;
nogenik (tdk langsung )
Senyawa yg mengalami 0lkilasi langsung bereaksi dg D/0(*arsinogenik langsung)
Substrat $rokarsinogen Senyawa poksida
poksida - " Dihidrodiol (tdk reaktif )
onooksigenase
poksida idrolase
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