Sulfotransferase (SULT) ee Cilmi-baarista DDI, Xasilloonida dheef-shiid kiimikaadka, iyo Ka-hortagga Enzyme

Erayada muhiimka ah: daroogada

1 IPHASE waxay soo saartaa

2 Cilmi-baarista Enzymatic ee Horumarinta Dawooyinka

Horumarinta daroogada, daraasadda phenotypes-ka dheef-shiid kiimikaadka iyo xannibaadda enzymes ee enzymes-ka dheef-shiid kiimikaadka sida CYP450, UGT, SULT, iwm waa muhiim. Cilmi-baarista phenotype-ka dheef-shiid kiimikaadka waxay isticmaashaa moodooyinka vitro-ga oo ay weheliso LC - Farsamada MS/MS si loo aqoonsado dariiqyada dheef-shiid kiimikaadka ugu muhiimsan, enzymes-ka dheef-shiid kiimikaadka muhiimka ah, iyo cabbiraadaha kinetic-ka (sida km/Vmax) ee daawooyinka, oo ay qiimeeyaan saameynta hidda-wadaha polymorphism-ka ee daawada shakhsi ahaaneed. Cilmi-baarista ka-hortagga enzyme waxay diiradda saartaa saameynta xannibaadda daawooyinka ama xeryahooda enzymes-ka dheef-shiid kiimikaadka (sida xannibaad la rogi karo/la-noqon karo), oo lagu cabbirayo qiyamka IC50/Ki si loo saadaaliyo.daroogada- isdhexgalka daroogada (DDI)khatarta. Daraasadahani waxay bixiyaan saldhig cilmiyaysan oo lagu wanaajinayo naqshadaynta daroogada, qiimaynta badbaadada (sida aqoonsiga dheef-shiid kiimikaadka sunta ah), iyo hagida dawooyinka saxda ah. Caqabadda xudunta u ah waxay ku jirtaa u beddelashada in vitro oo loo beddelo xogta in vivo iyo dareenka ogaanshaha dheef-shiid kiimikaad hooseeya. Mustaqbalka, moodooyinka horumarsan sida organoids ayaa loo isticmaali karaa si loo sii wanaajiyo isku hallaynta cilmi-baarista.

3 Sulfotransferase (SULT)

Sulfotransferase (SULT)waa nooc ka mid ah wareejinta oo kicinaysa wareejinta kooxaha sulfate waxayna ku lug leedahay dheef-shiid kiimikaadka xeryahooda endogenous (sida hormoonnada iyo neurotransmitters) iyo xeryahooda dibadda (sida daroogooyinka iyo wasakhowga deegaanka). Sulfotransferases waxay inta badan ku yaalaan cytoplasm iyo qalabka Golgi, oo ku lug leh sulfation substrates molecule yar yar (sida daawooyinka, hormoonnada, neurotransmitters) iyo molecules waaweyn (sida peptides, borotiinada, lipids, glycosaminoglycans). Sulfotransferases ayaa la ogaaday inay leeyihiin noocyo-hoosaadyo badan, oo ay ku jiraan SULT1, SULT2, iyo SULT4. Khalkhal la'aanta sulfotransferase waxay u horseedi kartaa dheef-shiid kiimikaad daroogada aan caadi ahayn, kansarka, cilladaha endocrine, iyo cilladaha neerfaha.

4 Dheef-shiid kiimikaad

Dheef-shiid kiimikaad (sidoo kale loo yaqaan dheef-shiid kiimikaad sulfation) ayaa door muhiim ah ka ciyaara daadinta vivo ee daroogooyinka waxayna aasaas muhiim u tahay horumarinta daroogada cusub iyo isticmaalka maandooriyaha caafimaad ee macquulka ah. Sulfotransferase aadanaha (sidoo kale loo yaqaan sulfatase) waxay leedahay noocyo kala duwan oo substrate ah oo jirka ku jira, inta badan waxaa loo qaybiyaa xubnaha sida beerka, xiidmaha yar, kelyaha, iyo sambabada. SULTyada caadiga ah ee bini'aadamka waxaa ka mid ahSULT1A1, SULT1A3, SULT1B1, SULT1C2iyoSULT1C4 ( shaxda 1). Inta badan substrates, sulfotransferase dheef-shiid kiimikaad dhexdhexaadin ah ayaa inta badan muujiya sifooyinka xakamaynta substrate caadiga ah; Heerarka fiirsashada substrate hoose ayaa caadi ahaan keena muujinta enzyme.

Shaxda 1 Qaybinta iyo shaqada qoyska sare ee SULT qayb ahaan ee jidhka bini'aadamka

5 Codsiyada Muhiimka ah ee SULT ee Horumarinta Dawooyinka

5.1 In Vitro Qiimaynta DDI oo ku salaysan dheef-shiid kiimikaad

Qiimaynta in vitro ee SULT dhexdhexaadin DDI waxaa inta badan lagu fuliyaa iyada oo la xushay inhibitors (sida quercetin, DCNP) ama nidaamka ensaymes recombinant ee cytoplasm hepatic bini'aadamka ama moodooyinka unugyada muujinaya SULT subtypes gaar ah. Naqshadaynta tijaabada ah sida caadiga ah waxaa ka mid ah:

Falanqaynta phenotype dheef-shiid kiimikaadka: Ku qiyaas heerka jiilka dheef-shiid kiimikaad sulfated by LC-MS/MS oo xisaabi heerka xannibaadda (qiimaha IC50/Ki).

Saadaasha khatarta kiliinikada: Haddii xannibaaduhu si weyn u yareeyo wax soo saarka dheef-shiid kiimikaadka (heerka xannibaadda> 50%), waxay soo jeedinaysaa in ay faragelin karto nadiifinta daawooyinka ku xiran dheef-shiid kiimikaadka SULT, iyo in dheeraad ah in vivo ayaa loo baahan yahay.

5.2 SULT Daraasada Xasiloonida Dheefshiidka

Horumarinta mukhaadaraadka, daraasadda xasilloonida dheef-shiid kiimikaadka SULT waxaa lagu qabtaa in vitro (cytoplasm hepatic cytoplasm/APS) oo ay weheliso falanqaynta LC-MS/MS si loo go'aamiyo heerka sulfation daroogada iyo jiilka dheef-shiid kiimikaadka, la ogaado wax ku biirinta SULT-hoosaadka muhiimka ah, qiimeeya khatarta nadiifinta dheef-shiid kiimikaadka, iyo hagida hagaajinta qaabdhismeedka.

5.3 Cilmi-baarista Substrate-ka dheef-shiid kiimikaadka

Habka cilmi-baarista substrate-ka (habka aqoonsiga dariiqa dheef-shiid kiimikaadka) ee SULT waxay si toos ah u tixraaci kartaa naqshadeynta enzymes CYP, kaas oo marka hore isticmaala xakameynta kiimikada si loo eego noocyada hoose ee khuseeya, ka dibna ku xaqiijiya dib-u-habeynta hiddo-wadaha oo xisaabiya tabarucdooda qaraabada ah.

Mabda'a ugu weyn iyo dariiqa farsamada ee tijaabada ka hortagga kiimikada SULT waa in la qiimeeyo in dheef-shiid kiimikaad hooyada ama soosaarka dheef-shiid kiimikaadka la xannibay iyadoo wax laga beddelayo xannibiyeyaasha xulashada Quercetin iyo DCNP ee SULT ee nidaamka cytoplasm beerka bini'aadamka.

5.4 Cilmi-baarista Xakamaynta Enzyme

SULT waxay ku lug leedahay dheef-shiid kiimikaadka walxaha iyo daawooyinka badan ee endogenous. Haddii dawooyinka loo soo saaro si loo joojiyo dhaqdhaqaaqa SULT, waxaa jiri kara arrimo badbaado oo suurtagal ah marka la wadaago daroogooyinka. Mabda'a ugu weyn iyo dariiqa farsamada SULT enzyme inhibition assay waa in la isticmaalo nidaamka enzyme saafiga ah SULT si loo ogaado in wax soo saarka metabolite p-nitrophenol sulfate la xannibay iyadoo lagu darayo daawooyinka baaritaanka iyo substrates probe sida p-nitrophenol.

6 Gabagabo

Sulfotransferase (SULT) ayaa door muhiim ah ka ciyaara dheef-shiid kiimikaadka daroogada, daroogada- isdhexgalka daroogada (DDI), iyo qiimeynta badbaadada. Dheef-shiid kiimikaadka sulfation-ka ee ay dhexdhexaadiso waxay saamaysaa nadiifinta daroogada, firfircoonida, ama sunta (sida dheef-shiid kiimikaadka daawooyinka hoormoonka iyo wasakhowga deegaanka), halka daraasaadka xannibaadda enzyme ay saadaalin karaan khatarta DDI ee caafimaad. Marka la isku daro moodooyinka vitro (cytoplasm beerka, enzymes recombinant) iyo LC-teknoolajiyada MS/MS, tabaruca dheef-shiid kiimikaadka SULT nooc-hoosaadyada (sida SULT1A1, SULT2A1) waa la cadeeyn karaa, hagaya qaab dhismeedka daroogada iyo hagaajinta shakhsi ahaaneed. Mustaqbalka, moodooyinka horumarsan sida organoids waxay sii kordhin doonaan qiimaha tarjumaadda ee cilmi-baarista SULT, iyagoo siinaya shuruudo qiimeyn oo sax ah oo loogu talagalay xasilloonida dheef-shiid kiimikaadka iyo badbaadada horumarinta daroogada.

Tixraac

Li, Y., Lindsay, J., Wang, L. L., & Zhou, S. F. (2008). Qaab dhismeedka, shaqada iyo polymorphism ee cytosolic sulfotransferases. Dheef-shiid kiimikaadka daawada hadda, 9(2), 99-105.