KHOA HOC K? THUAT THU Y TAP XX S6 6 - 2013
CAC HdP CHAT ELECTROFIL, CAC GOC TH 00: SH HINH THANH, TiNH NGHV HAI VA BIEN PHAP PHONG CHONG
Phgm Khdc Hiiu, Nguyen Mgnh Tir&ng Chi hQi thu y ~ Dgi hgc nong nghiep Hd Noi Cdc chdt chuyin hda Electrofil, gay nhiem dgc cho tl bdo, td chiic. Thi du: Electrofil 2,5-Hexandion (tft chdt mp Id Hexan sinh ra) gdy dpc hai cho cdc axon thdn kinh, ddc bigt Id thdn kinh ngoai bien. Alhnalkohol, Paracetamol gdy hgi cho gan vi d trong ca thi, chiing hinh thdnh ngn cdc acrolein (cdc chdt gay hoai tii).
Ddng chu y la: N-acetyl-p-benzokinanimin du thua, Vinilchorid va Aflatoxin da hinh thanh nen cac epoxid gay ung thu, nhdt Id ung thu gan.
rat nguy hiem.
Cdc chdt chuyin hda Electrofil di tu Chloroform, Halothan (thudc gay me) tao thanh HCl, phosgen, Trifluoroacetyl de gay dpc cap tinh vd man tinh cho con vat.
Su cd mat cua chdt chuyin hda Electrofil khdng chi gay dpc hai tryc tilp, cap tinh hoac (va) man tinh ddi vdi cac con vat dung thudc, md cdn de lai cdc chdt ton luu trong cdc sdn pham ciia chiing, la nguy ca de dpa siic khde ngudi tieu diing. Nhiing ngudi Idm cdng tac chan nudi, thii y khdng thg khdng quan tam van dg nay!
Khi cdc chdt Electrofil sinh ra qud nhilu hoac thudng xuyen sinh ra; khi Cytocrom P450 khdng dii, cd the se lam vdo vdng bpnh ly nan gidi. Cdc thi du dudi day giiip ta hieu them vg cdu tao hda hgc cua cac chdt chuyen hda Electrofil vd tdc hai (ddc) ciia chung:
Trong cudc sdng hdng ngay cua con ngudi vd dpng vat nudi, cd rdt nhieu chat ngogi lai xam nhap vao ca the, gay dpc. Thi dy: CO, Nicotin, Dioxin (TCDD), cac muoi thiiy ngdn, thach tin.... Nhung cung cd rdt nhilu trudng hgp ngd ddc khdng phdi do cdc chdt ngogi lai (Xenobioticum) md do chinh cdc chdt sinh ra trong ca thi, bdi qud trinh chuyin hda, trao ddi chat. Nhftng qud trinh ndy dugc ggi Id "dgc hgi do qua trinh chuyin hda" (Toxcalasio).
Qud trinh "ddc hai do chuyin hda", thudng diay nhdt Id qud trinh phan img hda hpc tao ra cdc hgp chdt Electrofil vd cac gdc ty do.
1. Cac hpp chat Electrofil
Cac hgp chat Electrofil la nhiing phan tu CO chua cac nguyen tu thigu electron. NghTa la nhiing chat do cd mpt phdn hoac todn bd dien tich duong. Cac hgp chdt Electrofil se thyc hien cdc phan ling cpng hda tn vdi cdc chat cd chfta cdc nguyen tu loai nucleofil (giau electron) nhu S,N,0.v.v...
Cdc chat "dgc hai do chuyen hoa" hinh thanh trong CO the. C6 nhilu loai thudc sir dung trong lam sang, khi dua vdo ca thi, ciing se tham gia cdc qua trinh chuyen hda khac nhau va hinh thanh nen cac chat dpc, gdy hai cho td chuc khi quan hay cho toan bp ca thi.
Cdc hgp chdt Electrofil se dugc cdc enzyme cam dng d gan, nhat Id Cytocrom P-450 phan huy, lam mat di hau qua ddc hgi cho co the.
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KHOA HOC K? THUAT THO Y TAP XX S6 6 - 2013
Cic chfift chuyin hda Electrofil vjl si/ d^c h^l do chljng gdy ra
HijTp chat CHjCH Cholorofomi
F,C C H
Halothan
HjC = CHCL Vinylclorid
H,C - (CHj), - CHj
0
'0'
N H C O C H , ParacetamolC l i a U i i u y i n h i u {) C L _ ^ C
phosgene
CL Trifluoracetv-clond
H,C CHCL
/ \
Vmvclond-epoxid H,C C C H , C H , C C H ,
L •
2,5- hexadion OH
<>
N H C O C H , N-acerv-benEokinonimin
D^c h^i Dgc cho gan
ViSm gan mih\
d|ch (immuhepaiitis)
Angiosarcoma a gan
ViSm t h k kinb ng09i bidn
H091 tii gan
2. Cac goc t y do
Cdc gdc ty do Id nguyen nhdn ciia khodng 60 benh hiem ngheo d ngudi. Nd Id nguygn nhdn cua su ldo hod tg bao, lao hda ca the.
Phat minh ve gdc ty do va tdc hgi cua chung, ve cdc giai phdp dg giam thigu vd chdng cdc gdc tu do, da nhan giai Nobel ndm 1998.
2.1 Khdi nifm chung
Gdc ty do Id nhirng phan tu hodc nhiiTig mdnh phdn tu; md trgn vanh dipn tu ngoai cua nd, cd chua cdc dipn tir (electron) "dan ddc".
Cac gdc ty do dugc hinh thanh theo cac qua trinh dudi day:
Nhgn vdo 1 electron Mat di 1 elecuon
Phd \ d 1 lign kit cgng hda tri Ngudi ta qui dinh: ddnh ddu gdc ty do bdng dau cham "* "; de the hipn sy cd mat cua electron
"dan dpc" vd cung cdn dl thi hien sy tich dipn cua nd (ducmg hay dm).
X + e - ^ X ' X - e - - » X - * X : Y ^ X ' + Y'
Thi du : 1 logi thudc diet cd la Paraquat (PQ**). Thudc nay rdt dgc cho cdc md phdi. N6 se tao nen cdc gdc ty do bdng cdch nhdn them electron. Ddu tign thudc d dgng tich dien ducmg,
KHOA HOC K? THUAT T H C Y TAP XX SO 6 - 2013
tich luy vdo cdc tg bao phdi. Sau dd nd tiep nhan electron td cac Cytocrom P450 reductase va hinh thanh nen gdc monocation. Tilp theo, gdc monocation ndy Igi nhudng electron cho phdn tu Oxygen, tao ngn gdc anion subperoxit (Oj") dg lai trd thanh Paraquat ban dau (PQ**).
Chu trinh oxy hod khu (Redox) cua Paraquat (PQ++) Nguon electron (e-) tic NADPH-Cytocrom P450-reductase
Hau qud cua chu trinh la: 1 phan tft PQ-H- da san sinh ra hgn tuc nhieu gdc ty do subperoxyd (0/). Gdc 0 / phdn ung mgnh hem rdt nhieu lan so vdi gdc HO'. Nd gay ra hogi tft td chuc. Chat Doxorubicin ciang vdi ca chg tuang tu nhu Paraquat, gay hoai tii ca tim rat nang ne.
Cdc hgp chdt cd chua cdc nguyen tft gidu electron (cdc nucleofil) nhu cac chat cd luu huynh (S), cac amin tham, cdc hydrazm, cac phenol vd hydroquinon, khi mdt di electron se hinh thdnh nen cac gdc ty do boat dgng.
Cdc peroxidase se xiic tdc de chuyen hod chiing. Thi du mieloperoxidase cua cac loai bach cdu hat (granulocyt) cd the chuyen hda nhilu loai thudc, hogt chat, thdnh cdc chat ddc theo phuang thftc nay. Nhu Propiltiouracil, Metiraazol, Procainamid, Hydralazin, Hydroquinon. v.v...
Cac hgp chdt chuyin hda ddc hai nay lai chinh la cac chat cd vai trd lam xudt hien cdc gdc ty do va ddu ddc cac te bdo ca thi; trong dd cd cd cac bach cdu hgt (trong benh agranulocytosis va benh Lupus).
Ngudi ta cung nhan thdy trong vung thdp cua than cd mgt lugng Idn enzyme Prostaglandin- H-syntetase cd hogt lyc peroxidase cao. Vd chinh nd, ddng vai trd quan trpng trong vipc tao ngn cdc gdc ty do tft Phenacetin, Paracetamol va Para - aminophenol gay dpc hai cho than.
Vdi cac chat cd lien ket cpng hda tri (Vi du:
CCl^, HjOj...) khi nhan them dien tu nd sg bi bien ddi nhu sau:
Vdi CCl^
CCl: Cl + e- - . [CI3C :C1] ^ Cl^C' + Cl Ngudn electron d phdn ling nay cGng dugc cung cdp tft citocrom P450. Gdc ty do Triclorometyl (CI3C.) gap phan tu Oxygen, hinh thanh ngn gdc Triclorometylperoxi (CI3COO,).
Goc ndy cd tdc dyng Peroxi hda ragnh cac lipid vd cudi ciing la gay nen hoai tft gan.
* Vdi HOOH ( H p j )
Cac ion kim logi, dac biet la Fe**, cd tdc dyng cam iing, gdy bien ddi
HO- OH + Fe^ ^ F e ^ + [HO : OH]" ^ HO + 0H
Ngudi ta gpi phan ung nay la phan irng Fenton. Phan iing tao ra gdc ty do Hydroxyl (HO") cue manh. CJ ddy 1 td hgp cac ylu td ddc hai cimg tac dgng 16n ca the, dd Id: HO*; OH";
Fe*** (Sdt hda tn 3) va chinh ca HOOH.
Trong chu trinh Oxy hda khu (Xem so do Chu trinh oxy hda khu ddi vdi Paraquat d tren)
Peroxid-anion {0.[) se tdi tgo lai HOOH theo ca che sau:
0 , + 2H*
, O j + 0 f ..HOOH
HOOH Igi tdi diln qua trinh tao gdc ty do ndi tren mdt each tuan hodn lien tyc. Ngudi ta da chftng minh rdng cdc O^ciing cdn dugc tao ra bdi cdc hoat dpng thyc bao./.
