Tinh da hinh ho enzym cytochrom P450 va cac phan iing co hai

• Quan ly - Trao doi

"^Dirgc di truyen hoc:

Tinh da hinh ho enzym cytochrom P450 va cac phan iing co hai cua thuoc

Biii Thanh TiingS Le Thi Thu Hu-ffng', Pham The Hai^

Nguyin Thanh Hai'*, Tir Minh Koong^

'Khoa Y Duac, Tnrdng Dai hoc Quoc gia Hd Npi ' Trudng Dgi hoc Dirac Hd Npi

* E- mail: haipharm@yahoQ.com

Summary

Adverse drug reactions (ADR) occur quite often. Ttie main cause is supposedly traced to genetic factors In pathogenetic view, many current researches have been focusing on the role of the genetic polymorphism of the cytochrome P450 enzymes. The polymorphism of the enzyme cytochrome P450 expression exert much impact on the preclinical stage of drug development. However, limited is the prediction of ADR in terms of direct clinical impacts of polymorphism PASO. In addition, clinical efficiency and efficacy/cost of polymorphism genotype P450's researches prior to prescribing have not been convincingly demonstrated.

Therefore, more studies are needed to apply the enzyme polymorphism of the cytochrome P450 genotype to prescribing. This should become routine in clinical practice to reduce ADR.

Keywords: Cytochrome P450 enzymes, polymorphism, ADR, adverse drug reaction.

Dat van de

Phan i>ng cd hai cua thudc (tieng Anh la Adverse Drug Reactions - ADR) la mdt trong cac van de dang lo ngai khi si> dyng thudc. Theo To chdc Y te the gidi - WHO, "Phan dng cd hat cua thudc Id mgt phan dng dgc hai. khong dinh triFocva xudt hien d lidu thudng dung cho ngu-di de phdng benh, chan doan hoac chda benh, hoac lam thay doi mdt chdc nang smh iy". Hang nam, ty le benh nhan phai nhap vien do cac ADR ngay cang tang.

Cac vdn d l cua ADR con lam tang mdc do phdc tap va chi phi, giam toe do qua trinh nghien ci>u va phat trien thudc mdi. Cac ADR du-g-c phan ra lam 6 loai [A (tang len}, B (la), C (man tinh), D (cham), E (ngu'ng sd dyng - cai thudc), F (thdt bai trong dieutn)] Tuy nhien, hien nay cd hai loai ADR du'p'c nghien cu'u ky i'l, Loai phd b i l n nhat cb lien quan den tinh chdt du'p'c ly cua thudc hoac khi si> dung thudc d lieu cao, dwac goi la loai A (vi du, hien tuang tang du'dng huylt do insulin hay hoai t d gan do paracetamol, chay mau du'dng tieu hda do thudc chdng viem khdng steroid (NSAIDs),..v,v) Cac ADR loai A co the d y doan tru'dc du-ac du'a tren tinh chat dugc ly cua thudc va cac thd nghiem

tien lam sang. Loai ADR thd hai, loai B, hay phan dng di dng, qua mdn xay ra a mgt so rat ft cdc benh nhan vdi lieu dung bat ky va thudng khbng lien quan d i n cdc tinh chat dipgc ly cua thudc. Mbt s6 vi dy cua ADR loai B la hien tugng phat ban do thuoc, phan dng qua mdn vdi penicilin, viem gan do hatothan.,,v,v. Mac du it pho b i l n hc^n so vdi ADR loai A, ADR loai B thudng gay ra mgt so hgu qua nghiem trgng vi khong the d u doan ducfc td cac thilc nghiem t i l n lam sang. Cf thdi diem hi?n tai, khoa hpc chua d y doan d u g c chinh xac benh nhan co nguy ca gap ADR loai B hay khdng. Cdc ADR loai B la mgt trong cac nguyen nhan pho bien de thu hdi hoac loai bd mdt thudc khdi thi trudng.

Gdn day, tai Viet Nam, khai niem Dugc di truyen hpc (Pharmacogenomics) da du-ffc gidi thieu i^l Day la mgt ITnh v y c khd vd cdn mdi, hua hen se tao ra mdt cupc each mang trong nghidn CU'U phat tnen thudc va trong chi dinh sd dyng thudc, Bai nay tap trung tdng quan ve Dugc di truydn hpc trong khfa canh phan iJng cd h^i ciia thuoc, qua viec danh gia moi lien quan gida d|c tinh di truyen - tinh da hinh cua CYP 450 - phdn dng CO hai cua thuoc.

T.AP CHi DL ( ; c HQC - 9/2014 (SO 461 NAM 54)

• Quan ly - Trao doi

N h y da biet CYP450 chju trach nhigm chuyen hda nhieu chdt ngi sinh va ngoai smh, trong dd cd thudc. Vi vgy, chung CM anh hudng nhieu d i n chuyen hoa, t u a n g tdc va tac dung cua thudc.

N h i l u nghien cu'u da chi ra rdng chung Id nguyen nhan chinh gay ra ca cac ADR loai A va loai B i^'.

CYP450 rcit da dang, va cd tfnh da hinh di truydn ldn, vd la bieu hien cua tfnh da hinh di truydn.

Mgt trong so cac van de Idn cdn d u g c giai q u y l t la mgt lien hg gifl'a he gen - bieu hien CYP450 - va cac ADR loai A vd lo?i B.

C y t o c h r o m P450

Cytochrom P450 (CYP450, CYP) la mgt thuat ngd chung chi mpt nhdm enzym oxy hda khii cd lien quan, nhu'ng khac biet, co vai tro quan trpng trong sinh ly dgng vat eo xuang sbng.

CYP450 chii yeu xuc tdc cho cdc phan dng oxy hda, du'a mgt nguyen t d oxy vao ca chat (enzym monooxygenase, oxidase va peroxidase,,..), ngoai ra CYP450 cung co the hoat dgng trong cac phan dng khu' '''l

CYP450 hign cd gan 60 hp khac nhau vd du'Q'c chia thanh ba nhbm chfnh, Mbi thanh vien cua mgt hg cd chya cac acid amin tu'ang t y nhau.

CYP450 du'oc danh sd va chu de bieu hign s y t i l n hda chung cua hp. Nhdm dau tien, bao gom cac hg CYP 5- 59 cb ai lyc cao vdi chat ngi sinh, du'Q'c bao ton tdt trong suot qua trinh tien hda.

Nhdm thd hai, bao gdm cac hg CYP 1- 3, cd di lyc thap hcyn vdi ca chat va ft d u g c bao tdn trong tien hda, Nhdm thd ba, bao gom hp CYP 4, chii yeu chuyen hda acid beo, cac ca chat hen quan, va mpt sd xenobiotic. Cac hg CYP 1- 3 tham gia

vao khoang 70 - 80% cac chuyen hda b u d c ddu cua thudc i^. Hdu h i t cac enzym trong hp CYP 1 - 3 cd tac dyng xuc tac khac nhau giua cac ca the khac nhau, Mdi ddng phan CYP cb the tao ra cac chdt chuyen hda khac nhau. Mgt xenobiotic cd the d u g c c h u y i n hda bdi ddng phan khac nhau cua mgt CYP thanh cac san pham gdn gidng hoac khdc nhau. Cac enzym thupc hp enzym CYP 1-4 cd the cung cd tac dung tren cung mot ca chat.

Cac enzym quan trpng nhat tham gia vao qua trinh chuyen hda thubc la CYP2C9, CYP2C19, CYP2D6 va CYP3A4, trong khi dd cac ddng phan quan trgng lien quan den s y chuyen hda sinh hgc cua cac hda chdt va ddc biet la kfch hoat s y trao ddi chdt cua cac t i l n chat gay ung thu la CYP1 A, CYP1/\2, CYP1B1, CYP2A6, CYP2E1 va lai CYP3A4 Mdi day, chuang trinh giai ma he gen ngudi da tim thdy cac gen bieu hien hp CYP2 va CYP3 mai nhu CYP2R1, CYP2S1. CYP2U1 va CYP3A43. hien dang nghien cdu v l chdc nang va tam quan trong cua chimg,

Co han 11.000 thanh vien ciia CYP450 da du'gc xac dinh cau true tinh d i n nay. Tuy nhien chi CO 57 loai cd vai trd quan trpng trong chuyen hba thuoc (bang 1), Phdn Idn chung cb hen quan den chuyen hda cac sterol, vitamin A va D i^'. Khoang mbt phan tu' trong sb 57 CYP450 nay chiu trach nhigm chuyen hda cua cac "xenobiotic" (cac hgp chat hba hpc ngoai smh hoac thudc) S6 lugng CYP450 chuyen hoa cac xenobiotic a ngudi thay ddi rdt Idn giija cac ca the, tham chi mpt sd ca the do dl truyen con khbng cb mgt sd loai trong s6 CYP450 neu tren.

Bang 1 : Phan loai CYP450 cua ngudi theo cac nhdm ca chat chuyen hoa chinh sterol

1B1 7A1 7B1 8B1 11A1 11B1 11B2 17A1 19A1 21A2 27A1 39A1 46A1 51A1

Xenobiotic I A I 1A2 2A6 2A13 2B6 2C8 2C9 2C18 2C19 2D6 2E1 2F1 3A4 3A5 3A7

Acid beo Bicosanoid 2J2 4F2 4A11 4F3 4B1 4F8 4F12 5A1

8A1

Gen mS h6a cho CYP450 v^ nhimg enzym cOa Chung cfupc chi dinh vdi thiT

Vitamin Chwa ro 2R1 2A7 24A1 2S1 26A1 2U1 26B1 2W1 26C1 3A43 27B1 4A22

4F11 4F22 4V2 4X1 4Z1 20A1 27C1

' chir Viet tk CYP, theo sau bai mot s6 fy A-r^p chi ho gen. m^t chif c^i viet hoe chi ho phu va mot so A-rap chi mot gen d^c biet

TAP C I I I D U p C HQC - 9/2014 (SO 461 NAM 54)

• Quan ly - Trao doi

CYP450 ddng vai trd quan trgng nhdt trong cac enzym ciia qua trinh chuyen hda sinh hgc giai doan I. Do vi trf xuc lac tren CYP450 cd kha nang thay ddi cau true khdng gian Idn han so vai cac enzym khac nen chung tham gia n h i l u phan ung xuc tac han ^. Mdt vi dy Id CYP3A4, do cd vi tri lien k i t vdi n h i l u co chdt cd kich thudc ldn va linh hoat, nen cd kha nang xiic tac cho cac ca chat cb kich thudc tu'ang ddi Idn vdi trgng lugng phan t d > 1000 Da, hoac cd the vdi hai hoac ba phdn to- hO-y ca nhd hon Cac CYP450 hdp thu anh sang cd b y d c sdng gdn 450 nm khi gdn vdi carbon monoxid (CO), cho ra phu'c hgp cd mau

hdng, nen ten cua chung co nghta la vj tri "sact6 450" hay "mau hong 450". Chu' P d day cd ngiiTa la "pigment" (sdc to) hay "pink" (mau hdng).

CYP450 du'gc phan bo d hdu het cac mb vi ca quan (gan, ruot, phoi, than, nao, cac te bao lympho, va nhau thai) vdi ty le khac nhau. Niiilu nhdt trong mang lyd'i ngi chdt d gan, day ciing la trung tam chuyen hda chfnh ciia thudc. Bang 2 giai thieu cac CYP450 chfnh d gan chuyen hba mgt sd thudc. IVlgt s6 CYP450 cd the cd ndng dp t u a n g ddi cao tai mgt s6 vj trf khac, vf du CYP3A4 d y g c tim thdy nhidu trong niem mac ruot non.

Bang 2: Cac CYP450 chinh a gan chiu trach nhiem chuyin hoa thuoc

Co-chat (Thuoc) Chat ttoat hoa

1A2 Paracetamol, cafein, ondansetron. Ethyl hba phenacetin phenacetin, tacrin, tamoxifen, theophyllin

Furafyllin Khoi thuoc la, thiJc an chay 2A6 Coumann, nocotin Hydroxyl lioa tai vi tri 7 Ditiocarb sodium

cua coumarin 209 Diclofenac, flurbiprofen, losartan,

phenytoin, piroxicam, tienilic acid, tolbutamid, torasemid, (S)- warfarin

Methyl iiydroxyl hba Sulfaphenazol Barbiturat, tolbutamid rifampicin (rifampin)

2C19 Diazepam. (S)- mephenytoin, omeprazol, Hydroxyl hoa tai v\ tri 4 pentamidin, propranolol, (R)- warfann cua (S)- mephenytoin

2D6 Bufuralol, codein, debrisoqutn, Hydroxyl hba tai vj tri 1' Quinidin, ajmalin desipramin, dextromethorphan, encainid, cua bufuralol

fluoxetin, halopendol, imipramin, nortriptylin, paroxetin, propafenon, propranolol, spartein

2E1 Paracetamol, caffein, chlorzoxazon, enfluran, theophyllin

3A4 Benzphetamin, clarithromycin, codein, cyclosponn, dapson, diazepam, erythromycin, felodipin, tacrolimus, indinavir, lovastatin, midazolam, nifedipin, carbamazepin, losartan, quinidin, taxol, terfenadin, verapamil

Hydroxyl hba Ditiocarb sodium chlorzoxazon

Hydroxyl hoa tai vi tri 6|3 Gestoden, testosteron troleandomycm,

L- 754.394.

ketoconazol.

itraconazol

Ethanol, isoniazid

Barbiturat, rifampicin.

dexamethason.

carbamazepin

Cac CYP450 cd tinh da hinh di truyen Idn.

Dieu nay co the khdng anh h y d n g tryc tidp den chdc nang enzym; tuy nhien, viec phat hien cua

cac da hinh do rat quan trgng vi chung cd the liSn quan den qua trinh mat can bdng vdi mpt chirc nang bidn the.

T.\P CHi DU<?C HQC - 9/2014 (SO 461 NAM 54)

• Quan ly - Trao do!

Cdc da hinh CYP450 co the dan den:

• Ldm mat hoat tinh, dieu ndy cd the xay ra do bj huy hoai gen, hodc neu da hinh thay ddi qua trinh cat - noi protein, lam thay doi vj tri bat d^u phi§n ma hoac thSm vdo mgt amino acid cd hai vao cau true;

• l_am giam hoat tinh. nhu vi du vdi CYP2C9 * 2;

• Lam thay ddi hoat tinh, khi cac da hinh a vj tri kich hoat lam thay tinh ddc hieu ca chat, nhu da thay vdi CYP2D6*17 va CYP2C9*3, hay cd s y thay ddi trong qua trinh tao hinh protein (protein folding) d i n den cd hoat tfnh dac hieu vdi mdt ca chat khac, vi du, vdi CYP2D6*10;

• Ldm tang hoat tinh cua enzym, khi cd s y trimg lap gen, vi du CYP2D6 * 2xN,

Tac dung cua mpt da hinh CYP450 trong qua trinh thdi t r d ciia thuoc lien quan chinh den giai doan quyet dinh dp thanh thdi cua chat chuyen hoa. Khi do thanh thai h\ anh hudng bdi qua trinh chuyen hda phy thugc vao mdt CYP450, mpt da hinh Idm giam hoat tinh enzym se lam gidm dg thanh thai, dan den tang thdi gian ban thdi Idm x u l t hien cdc phan dng cd hai theo lieu. Khi nhieu enzym ciing tham gia chuyen hda thuoc, thi mdt da hinh se cd it anh hudng han do do kha nang dan den phdn d'ng cd hai se it han. Tif dd, cdc da hinh CYP450 co nhieu kha nang ddn den phan U'ng cd hai loai A han la loai B i^l

Mdi CYP450 cd tinh dac hieu vdi nhieu ca chdt, nhung iai cd each chuyen hda rieng vdi tirng ca chdt cu the. Dieu nay cho phep chuyen hda nhidu hgp chdt hda hgc vdi cau true khdc nhau. Ngodi ra, cdc enzym nay cd co chd dieu hda khdc nhau de kiem scat hoat do C a chd dieu hda nay cd the la cac chdt cd tac ddng hoat hda hoac iPc chd enzym. V i du, CYP1A2 chuydn hda mpt so chdt gdy ung thy trong khdi thudc Id va d u g c hoat hba bdi chinh cdc chat dd. Mdt so CYP450 khdc dipgc hoat hda bdi cac loai thudc nhiP thudc an thdn barbiturat, thudc chong co giat va rifampicin. Tieng enzym cung cd tinh chgn Igc vdi cac ca chdt khac nhau. V i du, sulfaphenazol Id mgt chat uc chd dac hieu ciia CYP2C9, trong khi quinidin la mgt chdt LFC chd manh va chgn Ipc cua CYP2D6. Mdt sd CYP450 cd dac diem dl truyen da hinh. Tan sd cua cac da hinh do thudng khac nhau, phy thudc dang ke vao tdng dan tgc, Nhiing khdc biet di truydn dd anh hiFong ddn hoat tinh ciia enzym, co the lam giam hoac mat hoat tinh. Neu benh nhan la ngifdi "chuyen hda chdm" thi cd nhieu nguy ca bi anh hifdng bdi phan dng cb hai vdi cac thudc bi chuyen hda bdi cac enzym dd.

Ba ho CYP 1,2,3 ddng vai trd chinh trong qud trinh chuyen hda cac thudc. Bang 3 liet ke cac da hinh di truyen ciia cac CYP gay ra cac phan d'ng cd hai ciia thudc-

Bang 3: Cac da hinh di truyen cua CYP gay ra cac phan dng cd hai cua thuoc '^i

CYP CAc bien the allel va tan so Vi du ve cac ADR lien quan den cac bien (he allel CYP CYP1A2*1F(68%)

CYP2D6M (12-/21%) CYP2D6'5 (4 - 6%) CYP2D6M0(1 -/2%) CYP2D6*17(0%)

CYP2C19'2(13%) CYP2C19*3(0%) CYP2C9"2(8-/13%)

CYP2C9*3(7-/9%)

CYP3A4*1B(5,5%)

Thuoc chbng loan thdn, roi loan van dbng mupn Propafenon, loan nhip tim IVletoprolol, cham nhip tim Nortnptylin, gay nham lln Opioid, gay nghien Phenformin, nhiem acid lactic

Perhexilen nhiem dpc gan Diazepam, buon ngu keo dai Mephenytoin, dpc tinh

Warfarin, xuat huyet Phenytoin, ddc tinh phenytoin

Tolbutamid, hg dudng huyet Epidophyllotoxins, lien quan den dieu tn benh bach cau

I . \ P C H i DUgfC HOC - 9/2014 (S6 461 N.\M 54)

• Quan ly - Trao do!

Cytochrom P450 1A2 (CYP1A2) CYP1A2 so vdi cac CYP450 khdc cd vai trd tuang ddi nhd trong s y chuyen hoa thudc, mac du chiem 15% tdng sd ham lifgng CYP trong gan nhu'ng chi tham gia chuyen hda khoang 5% cdc ioai thuoc du'gc su' dung'^i, CYP1A2 tham gia vao chuyen hda mdt sd loai thuoc bao gdm paracetamol, theophyllin, propranolol va mgt so thudc chdng loan than nhir olanzapin va clozapin'^"'. Mdt nghien cdu cho thdy vai trb ciia da hinh CYP1A2*1F trong viec anh hydng gay ra rdi loan van ddng mupn, mgt phan irng cd hai xay ra khi siK dyng thudc chdng loan thdn man tinh tren khoang 20 - 30% sd benh nhan ^''\ Bieu hien dac trung la cdc cu' dgng ngoai y mudn ciia cac ca mieng, mat va ddi khi la d than va t d chi, va cd thd khdng the dao ngugc duac d nhidu benh nhdn.

Cytochrom P450 2D6 (CYP2D6) CYP2D6 la ddng phan CYP ddu tien d u g c phat hien d u a c (ban ddu d u g c ggi la debrisoqum hydroxylas)!^^!, C a sd da hinh di truydn da d u g c xac djnh rb: cd han 70 bign the allel d y a c xdc dinh, trong do cd hai bidn the pho bien nhdt CYP2D6*4 va CYP2D6*5 CYP2D6 cd vai trd quan trpng trong viec chuyen hda thudc han so vai CYP1A2, dam nhiem viec chuyen hda khoang 25% tong s6 cac thuoc s d dungi^i. Trong do, chii ydu la cac thudc chong loan nhjp (encainid, flecainid, propafenon, spartein); thuoc chong trdm cam (amitriptylin, clomipramin, desipramin, fluoxetin, imipramin, nortnptylin, paroxetin, sertralm, venlafaxin);

thuoc chong loan thdn (fiuphenazin, flupenthixol, haloperidol, perphenazin, nsperidon, thioridazin, zuclopenthixol); thudc chan kenh beta (alprenolol, bufuralol, metoprolol, propranolol, timolol); cac thuoc giam dau opiat (codein, dextromethorphan, ethylmorphin, tramadol).

Viec xac djnh cac da hinh trong gen bieu hi^n CYP2D6 cd mgt tdc dgng Idn den qua trinh phdt trien thudc, va do do cd anh h u d n g gian tiep tdi thyc hanh lam sang. Cac bien the allel CYP2D6 cd thd ddn ddn phan d'ng cd hai thdng qua cac c a chd khac nhau. Cac chdt chuydn hda cua perhexilen (thuoc chdng dau thdt nguc) it bj anh hudng bdi CYP2D6, vi thd cd xu hyang giamdO thanh thai va bi tich tu trong nhy gan va cdc mfi than kinh den nhiem dpc gan va ton thuang than kinh ngoai bien^l Tuy cd nhieu bao cao ve cac phan yng cd hai lien quan ddn cac chdt chuyen hda it bi anh hifdng cua CYP2D6 nhung van chua cd nhieu thay doi trong thyc hdnh lam sang.

Cytochrom P450 2C9 (CYP2C9) Cac thanh vien trong hg CYP2C chidm 15- 20% tong s6 ham l y g n g CYP ciia gan, va chuyen hda khoang 20% cua tat ca cac loai thudc hien dung[i3]. CYP2C9, mgt thanh vien chfnh cua hp CYP2C, dam nhiem cho s y chuyen hda mgt s6 thudc nhif warfarin, phenytoin, losartan, tolbutamid, va cac loai NSAID khac nhaui'**'.

Cac bien the allel khac nhau cua gen bieu hign CYP2C9 da d u g c xac dmh, hdu het cac nghien cifu da du'gc xac djnh bidn the allel CYP2C9'2 va CYP2C9*3, co hoat tinh t d 5 den 12% so vdi nguyen dang CYP2C9*1f'3i,

Cac bidn the CYP2C9*2 va CYP2C9*3 deu cb tac dung lam giam dp thanh thai cua warfarin va phenytoin (so vdi nguyen dang CYP2C9'1), va do dd cac benh nhan cd cac bidn the allel nay se dup'c yeu cdu SCP dyng lidu thdp cac loai thu6c nay (bang A^^^h Viec kiem soat dieu trj warfarin thudng gap nhieu khd khan a nhung benh nhdn nay, cdc benh nhan thudng cd hien tuang chay mau, Nhidu benh nhan vdi cac bien the allel bilu hien CYP2C9 cd hien t y g n g ngg ddc phenytoin dd d y g c ghi nhan^'^i.

Bang 4: Anh huv'ng cua bidn thS allel bieu hien CYP2C9 tren lidu warfarin va phenytoin""

Loai gen CYP2C9 Lieu trung binh warfarin (mg) Lieu trung binh phenytoin (mg) CYP2C9'1'1

CYP2C9*1*2 CYP2C9-1'3 CYP2C9*2*2 CYP2C9*2'3 CYP2C9'3*3

3,4 3.6

287 201 196 217 175 khong xac djnh

TAP CHi D U O C HQC - 9/2014 (SO 461 NAM 54)

• Quan ly - Trao doi

Cytochrom P450 3A4 (CYP3A4) Cdc thanh vien cua hg CYP3A chidm 30% tong so hdm lugng CYP va CYP3A4 la hg enzym dwgc nghien ciru nhieu nhat. Hg enzym nay la mdt trong nhOng CYP450 cd nhieu nhdt trong gan, tham gia xdc tdc hon chuc phdn yng hda hgc khac nhau va ddng vai trd quan trgng trong chuyen hda cua hdng tram ca chat vdi kich thifd-c va cau tnic hda hgc rat khac nhau, bao gdm han 37% cac loai thudc pho bien nhat d u g c sif dungi''^. Mac dii cb nhieu bien the gida cac cd nhan trong bieu hien cua CYP3A4 (ddng phan chinh ciia hg CYP3A), nhyng didu ndy khdng lien quan den s y da hinh ciia cdc gen ma hda'^'.

Oa h i n h CYP450 va phan u'ng co hai loai B Cac phan ifng cd hat loai B cb hen quan ddn nhieu yeu to sinh ly benh phirc tap. Vai trd cua CYP450 vai nhiing phan ifng co hai loai nay da d u g c danh gia nhidu, Cac CYP450 chuyen hda thuoc tao thdnh chat chuyen hba khdng cd hai h o a c c d hai.

Neu chat chuyen hda cd hgi khong difgc chuyen hoa tiep thdnh chat khdng dpc, chiing se lien ket voi cac dai phan tif vd dan den ngg dgc tryc tiep, hoac hoat dgng nhu cac hapten, dan den dgc tfnh midn djch. Vi vay trong truong hgp ndy, benh nhan cb bidn the allel vdi bieu hien hoat tinh CYP450 giam se hinh thanh cac chat chuyen hda dpc hai ft hon, va do do se cd ft nguy CO gdp phan Ung cd hai loai B Ngugc lai, nhifng bgnh nhan vdi mgt gen bieu hien CYP450 d u g c khuech dgi, vf dy CYP2D6* 2xN, se cd nguy co cao, Cdc nha khoa hgc tin rang cac gen tu'ang tac vdi cac yeu td moi trudng co kha nang tham gia vao cac yeu td di truyen lien quan den phan ifng cd hai logi B^^K Moi mgt gen bieu hien CYP450 cd the khdng la dieu kien can vd dii de t y gay ra phan ifng cd hgi loai B, nhyng s y hien dien cua cac gen nay Idm tang nguy co phat trien phan u-ng cd hgi dd. Cho den nay, chua cd nghien cifu ndo Chung mmh rdng da hinh CYP450 la yeu to quan trgng gdy ra phan ung cb hgi Ioai B.

Tdc d g n g lam sang cua da hinh CYP450 t r o n g cdc phan u'ng co hai cua t h u d c

Oa cd nhirng bifdc tien Idn ve hieu biet co s d dl truyen trong s y bien doi hoat tinh cua CYP450 giu'a cdc cd the dan den khai niem "ca the hda dieu trj", Tuy nhien, trong thyc te dieu

nay khdng de ap dung tren thyc hanh Idm sdng.

Nguyen nhan la do truoc khi ke don thudc cho benh nhdn, thdy thudc ehu'a cd thdi quen xac dinh kieu gen hoac kieu hinh de xac djnh dirge thudc cd bj chuyen hda bdi mdt da hinh bieu hien ciia CYP450 hay khdng. Cb nhidu iy do cho vdn de ndy:

1. Phuong phap xac djnh kieu hinh va kieu gen bieu hien CYP450 thyong khdng cd sdn.

Ngoai ra cac kdt qua xac dinh kieu hinh cung cb the mang tinh da nghia; bieu hien tac dung cd the bj anh hydng bdi cac loai thudc dimg ddng thdi, tifC la cd thd cb mdt s y thay ddi trong s y sao hinh. Hon nOa, phifong phap xac djnh kieu gen thi thifdng ddt t i l n , anh hudng den can ddi giu'a chi phf/hieu qua didu trj.

2. Hien tai cd ft thdng tin k i t hgp giifa di truyen hgc va difOC ly hoc, ITnh vyc canh gidc du'gc hien van chya thyc sif phat trien,

3. Cdc phan dng cd hai da difgc bao cao d nhii'ng benh nhan cd allel hogt tinh thap, trong da so cac trifong hap la nhe va khdng nghiem trpng (vi dy nhu lam nhjp tim cham khi dung metoprolol), Mac du phan ifng cd hai nghiem trgng cung cb the xay ra, nhirng hiem khi gay tif vong. Ngoai ra, ddi voi hau hdt cac loai thudc, chiing ta cung cb the sif dung cac logi thudc khac de thay the mot each d l dang, Vi du, d mgt benh nhan bi giam nhjp tim khi dung metoprolol, cd the tranh bdng each cho si> dung atenolol thay thd Do db, khi mbt loai thudc thay the cd san va phan ung co hai la nhe, se khbng the chifng minh d u o c la viec nghien cifu kieu gen da hinh bieu hien CYP450 truoc khi didu trj bdng thudc la that s y can thiet. Han nira, cb mpt sd loai thudc khi thay ddi each sir dyng cb the cai thien d u a c hieu qua dieu tri mgt each rb rang. Vi dy, vdi warfarin, viec kiem soat chdng dbng cb the cai thien d u o c bdng each sif dyng may tinh trong hd trg diing thudc.

4. Trong nhidu trudng hgp, mdi lien he gitfa mbt da hinh CYP450 va phan dng cb hai nhidu khi khbng d u g c chu y Vi bu, phan dng co gigt la mgt trong nhdng bidn chii-ng chinh ciia didu tn chdng loan than. Do nhieu thudc chong loan than d u g c chuyen hda bdi CYP2D6, mgt gia thuyet rd rang de kiem tra la ligu nhung benh nhan it chuyen hda CYP2D6 cd nguy co cao phat tnen TAP CHi DUOC H O C - 9 / 2 0 1 4 (SO 461 NAM 54)

• Quan ly - Trao doi

nhij'ng tac dung phu hay khdng, Tuy nhien dieu nay v i n chua d u g c danh gia vd mmh chdng.

5. De dp dyng d y g c chuyen hda thudc bd'i mgt da hinh CYP450 tren t h y c hdnh lam sang thi dieu quan trgng Id chdng minh d u g c hieu qua lam sang, tdc la cdn phai lam viec trong mgt tinh hudng lam sang cu the.

Ket iuan

Cho den thdi diem hien nay, da c:d nhieu hieu biet quan trpng trong viec lam sang td c o so phan tif cua s y thay doi trong bieu hien va hoat tinh ciia CYP450. Tdc ddng chinh cua cdc kien thifC dd chu ydu tdi ITnh v y c nghien cdu phat trien thudc, qua viec xdc dinh cac da hinh CYP450 tham gia vao qua trinh chuyen hda cua thudc de lam can c d cho giai doan nghien cifu tidn lam sang. Tac dgng ciia cdc hieu biet do toi ifng dung dieu tn lam sang, mac dii co rdt nhidu then vpng, nhung van cdn rdt han chd,

Cac da hinh cua CYP450 cd nhieu anh hudng quan trgng tdi cac phan ifng cd hgi logi A cua thuoc, vi mdt gen duy nhat cd the quyet djnh d u g c SLf thanh thai cua thudc, do do cd the d y doan d u g c phan ifng cb hai mgt each thuan lgi.

Ngup'C lai, loai phan u-ng cd hai loai B cua thudc la qua trinh gdm nhieu bifoc, va tac ddng chuyen hda thuoc do CYP450 cd the bi chdng cheo bdi cdc da hinh CYP450. Do do, rdt can cb cac nghien cifu ve kieu gen bieu hien CYP450 trifoo khi ke don trong thyc hanh lam sang de danh gia tinh don nghTa ciia thbng tin vd danh gia hieu qua chi phi dieu trj.

Cac kidn thifc ve van de nay ngay cang tang se giiip cho qua trinh ke dan thudc cd co sd khoa hpc hon, dgc biet la ke don tren co s d dac tfnh du'gc di truyen hgc cua tifng nhbm benh nhan cu the, Didu nay se giup dam bao tdt hon quydn loi cho ngudi benh, giam sd trydng gap cac ADR, giam chi phi can thidt de xif ly hau qua do didu tri va nang cao chdt lugng d i l u tn.

Tai lieu thiam l(hao

1 Pirmohamed M, et al (1998), -Adverse drug reactions. BMJ, 316(7140), p 1295- 1298

2 Hai, N-T, P.TM, Hue va TM Koong (2014),

"Duac di truyin hpc: trien vpng va cac van d l dat ra", Tap ch/DL«Jcftpc, 4/2014. 54(456), p 2-6,

3. Pirmohamed, M. and B.K. Park (2001), -Genetic susceptibility to adverse drug reactions'. Trends Phamiacol Sci., 22(6). p. 298- 305.

4 Ortiz de Montellano, P R, (2010), "Hydrocarbon hydroxylation by cytochrome P450 enzymes", Chem.

Rev, 110(2), p. 932-948.

5. Ingelman- Sundberg M. (2004), "Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms", Naunyn Schmiedebergs Arch.

Pharmacol.. 369(1), p, 89-104.

6. R, Guengerich F, (2006), "Cytochrome P450s and other enzymes in drug metabolism and toxicit/', AAPSJ.8{np 101-111,

7. Pochapsky, T C , S Kazanis, and M, Dang (2010), "Conformational plasticity and structure/

function relationships in cytochromes P450", Antioxid Redox Signal. 13(8), p 1273- 1296.

8. Pirmohamed M. and B. K. Park (2003),

"Cytochrome P450 enzyme polymorphisms and adverse drug reaction", Toxicology. 192(1), p. 23- 32.

9. Wolf C, R and G. Smith (1999), Pharmacogenetics, Br. Med Bull.. 55(2), p. 366-386,

10. Pelkonen 0, et al. (1998), "Inhibition and induction of human cytochrome P450 (CYP) enzymes', Xenobiotica. 28(12), p. 1203-1253.

11. Basile V, S. et al. (2000), "A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia" Moi Psychiatry, 5(4), p, 410-417,

12- IVIahgoub A et al (1977), "Polymorphic hydroxylation of Debrisoquine in man". Lancet,.

2(8038), p, 584- 586

13. Lee C, R,, J. A, Goldstein, and J, A Pieper (2002), "Cytochrome P450 209 polymorphisms, a comprehensive review of the in-vitro and human data', Pharmacogenetics, 12(3), p. 251- 263.

14, Goldstein J. A, (2001), "Clinical relevance of genetic polymorphisms in the human CYP2C subfamily", Br. J. Clin. PharmacoL. 52(4), p. 349- 355, 15 Higashi M, K„ et ai. (2002), "Association between CYP2C9 genetic vanants and anticoagulation- related outcomes dunng warfarin therapy", JAMA. 287(13), p. 1690-1698.

16. Van der Weide J, et al, (2001), "The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement". Pharmacogenetics, 11(4), p, 287-291.

17, Zanger U M. et ai. (2008), "Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation", Anat.

Bioanal. Chem , 392(6), p. 1093-1108

{Ngay nhan bai: 02/08/2014 - Ngay duyet dang: 08/09/2014)

TAP CHi D U Q C HQC - 9/2014 (SO 461 NAM 54)