Sulfotransferase(SULT) yeDDI Research, Metabolic Stability, uye Enzyme Inhibition

Mashoko akakosha: zvinodhaka-kusangana kwezvinodhaka (DDI), sulfotransferase (SULT), enzyme inhibition, SULT metabolic, metabolic kugadzikana, munhu SULT1A1 enzyme, munhu SULT1A3 enzyme, munhu SULT1B1 enzyme, munhu SULT1C2, munhu SULT1C4 enzyme, munhu SULT1 enzyme enzyme, munhu SULT1E2 enzyme

1 IPHASE Inogadzira

2 Enzymatic Tsvagiridzo muKuvandudza zvinodhaka

Mukukura kwezvinodhaka, kudzidza kwemetabolic phenotypes uye enzyme inhibition yema metabolic enzymes akadai seCYP450, UGT, SULT, nezvimwe. Metabolic phenotype research inoshandisa in vitro modhi yakasanganiswa neLC-MS/MS tekinoroji kuona nzira huru dzemetabolism, key metabolic enzymes, uye yavo kinetic paramita (seKm/Vmax) yezvinodhaka, uye kuongorora kukanganisa kwegene polymorphism pamushonga wemunhu. Enzyme inhibition research inotarisa pane inhibitory mhedzisiro yemishonga kana makomisheni pama metabolic enzymes (akadai seanodzorereka / asingadzoreki inhibition), kuyera IC50/Ki kukosha kufanotaura.zvinodhaka - kusangana kwezvinodhaka (DDI)ngozi. Zvidzidzo izvi zvinopa hwaro hwesainzi hwekugadzirisa dhizaini dhizaini, kuongorora kuchengetedzeka (sekuona huturu hwemetabolites), uye kutungamira mishonga chaiyo. Dambudziko guru riri mukushandurwa kwe in vitro kuenda ku data ye vivo uye nekunzwa kwekunzwa kwematabolites akawanda. Mune ramangwana, mhando dzepamberi senge organoids dzinogona kushandiswa kuwedzera kuvimbika kwekutsvagisa.

3 Sulfotransferase (SULT)

Sulfotransferase (SULT)imhando yetransferase inokonzeresa kutamiswa kwemapoka e sulfate uye inobatanidzwa mumetabolism ye endogenous compounds (senge mahormone uye neurotransmitters) uye exogenous makomisheni (akadai semishonga uye zvinosvibisa zvakatipoteredza). Sulfotransferases inonyanya kuwanikwa mu cytoplasm uye Golgi apparatus, inobatanidzwa mu sulfation yediki molecule substrates (zvakadai semishonga, mahormone, neurotransmitters) uye mamorekuru makuru (se peptides, mapuroteni, lipids, glycosaminoglycans). Sulfotransferases akaonekwa kuti ane akawanda subtypes, kunyanya kusanganisira SULT1, SULT2, uye SULT4. Kusashanda zvakanaka kwesulfotransferase kunogona kukonzera kusagadzikana kwemetabolism yezvinodhaka, kenza, endocrine kusagadzikana, uye kusagadzikana kwetsinga.

4 Sulfation/Sulfation Metabolism

Sulfation metabolism (inozivikanwawo se sulfation metabolism) inoita basa rakakosha mukurasa zvinodhaka muvivo uye hwaro hwakakosha hwekuvandudzwa kwemishonga mitsva uye kushandisa zvinodhaka kukiriniki. Human sulfotransferase (inozivikanwawo se sulfatase) ine huwandu hwakawanda hwe substrates mumuviri, inonyanya kugoverwa munhengo dzakaita sechiropa, ura hudiki, itsvo, uye mapapu. Kazhinji vanhu SULTs vanosanganisiraSULT1A1, SULT1A3, SULT1B1, SULT1C2,uyeSULT1C4 (tafura 1). Kune akawanda substrates, sulfotransferase mediated metabolism inowanzoratidza maitiro ekudzivirira substrate; Low substrate concentration mazinga anowanzo konzera enzyme kutaura.

Tafura 1 Kugovera uye basa rechikamu cheSULT superfamily mumuviri wemunhu

5 Mashandisirwo Akakosha eSULT muKuvandudza Mishonga

5.1 In Vitro Kuongororwa kweDDI Kubva pane Metabolism

In vitro evaluation yeSULT mediated DDI inonyanya kuitwa kuburikidza neselective inhibitors (senge quercetin, DCNP) kana recombinant enzyme systems mumunhu hepatic cytoplasm kana masero emhando anoratidza chaiwo SULT subtypes. Kuedza dhizaini kazhinji inosanganisira:

Metabolic phenotype kuongorora: Kuenzanisa chiyero che sulfated metabolite chizvarwa neLC - MS / MS uye kuverenga inhibition rate (IC50 / Ki kukosha).

Kufanotaura kwekliniki yengozi: Kana iyo inhibitor inoderedza zvakanyanya kugadzirwa kwemetabolite (inhibition rate> 50%), inoratidza kuti inogona kukanganisa kubviswa kwezvinodhaka zvinoenderana neSULT metabolism, uye mberi mu vivo kusimbiswa kunodiwa.

5.2 SULT Metabolic Kugadzikana Chidzidzo

Mukuvandudzwa kwezvinodhaka, chidzidzo cheSULT metabolic kugadzikana kunoitwa kuburikidza ne in vitro incubation (hepatic cytoplasm/APS) yakasanganiswa neLC - MS/MS kuongororwa kuti ione zvinodhaka sulfation rate uye chizvarwa chemetabolite, tsvaga zvakakosha SULT subtype mipiro, kuongorora njodzi dze metabolic clearance, uye kutungamira kugadzirisa kwemaitiro.

5.3 Metabolic Substrate Research

Iyo substrate yekutsvagisa nzira (metabolic pathway identification method) yeSULT inogona kunongedzera zvakananga kune dhizaini yeCYP enzymes, iyo inotanga kushandisa makemikari inhibition kuratidza akakodzera subtypes, uye yozoaongorora nemagene recombinases uye kuverenga mupiro wavo.

Nheyo huru uye nzira yeunyanzvi yekemikari inhibition test yeSULT ndeyekuongorora kana maternal metabolism kana kugadzirwa kwemasabolite kunodziviswa nekugadzirisa zvakasarudzwa inhibitors Quercetin uye DCNP yeSULT mumunhu hepatic cytoplasm system.

5.4 Enzyme Inhibition Research

SULT inobatanidzwa mune metabolism yezvakawanda endogenous zvinhu uye zvinodhaka. Kana zvinodhaka zviri kugadzirwa kuti zvidzivise basa reSULT, panogona kunge paine nyaya dzekuchengetedza pakugovana zvinodhaka. Nheyo huru uye nzira yehunyanzvi yeSULT enzyme inhibition assay ndeye kushandisa SULT pure enzyme system kuona kana kugadzirwa kwe metabolite p-nitrophenol sulfate kunodzivirirwa nekuwedzera mishonga yekuongorora uye probe substrates yakadai se p-nitrophenol.

6 Mhedziso

Sulfotransferase (SULT) inobata basa rakakosha mumetabolism yezvinodhaka, zvinodhaka - kudyidzana kwezvinodhaka (DDI), uye kuongororwa kwekuchengetedza. Iyo sulfation metabolism inopindirana nayo inokanganisa kubvumidzwa kwezvinodhaka, activation, kana chepfu (senge metabolism yemishonga yehomoni uye zvinosvibisa zvakatipoteredza), nepo enzyme inhibition zvidzidzo zvinogona kufanotaura njodzi yekiriniki yeDDI. Nekubatanidza in vitro modhi (chiropa cytoplasm, recombinant enzymes) neLC - MS/MS tekinoroji, iyo metabolic mipiro yeSULT subtypes (yakadai seSULT1A1, SULT2A1) inogona kujekeswa, inotungamira dhizaini dhizaini optimization uye yemunhu mushonga. Mune ramangwana, mamodheru epamberi senge organoids anozowedzera kukosha kwekududzira kweSULT tsvagiridzo, ichipa yakanyatso ongorora maitiro ekugadzikana kwemetabolism uye kuchengetedzeka mukuvandudza zvinodhaka.

Reference

Li, Y., Lindsay, J., Wang, L. L., & Zhou, S. F. (2008). Chimiro, basa uye polymorphism yevanhu cytosolic sulfotransferases. Ikozvino zvinodhaka metabolism, 9(2), 99-105.