Sulfotransferase(SULT) mo le DDI Research, Metabolic Stability, ma le Enzyme Inhibition

upu autu: fualaau faasaina - fegalegaleai fualaau (DDI), sulfotransferase (SULT), enzyme inhibition, SULT metabolic, metabolic stability, tagata SULT1A1 enzyme, tagata SULT1A3 enzyme, tagata SULT1B1 enzyme, tagata SULT1C2, tagata SULT1C4 enzyme, tagata SULT1E1 enzyme, tagata SULT2A1 enzyme, tagata SULT2A1 enzyme

1 IPHASE E gaosia

2 Enzymatic Research in Drug Development

I le atinaʻeina o vailaʻau, o le suʻesuʻeina o faʻamaʻi faʻamaʻi ma le enzyme inhibition o enzymes metabolic pei ole CYP450, UGT, SULT, ma isi e taua tele. Metabolic phenotype suʻesuʻega faʻaaogaina in vitro faʻataʻitaʻiga tuʻufaʻatasia ma LC - MS / MS tekinolosi e iloa ai le auala autu metabolic, enzymes metabolic autu, ma o latou kinetic parameters (e pei o Km / Vmax) o fualaau faasaina, ma iloilo le aafiaga o gene polymorphism i vailaau patino. O suʻesuʻega faʻamaʻi faʻamaʻi e taulaʻi atu i aʻafiaga faʻalavelave o vailaʻau poʻo faʻapipiʻi i luga o enzymes metabolic (e pei o le faʻaaogaina / le mafai ona faʻaaogaina), fuaina o le IC50 / Ki e vaʻai ai.fualaau fa'asaina-feso'ota'iga vaila'au (DDI)tulaga lamatia. O nei su'esu'ega e maua ai fa'avae fa'asaienisi mo le fa'amaninoina o le mamanu o vaila'au, iloiloga o le saogalemu (e pei o le fa'ailoaina o metabolites o'ona), ma le ta'ita'iina o vaila'au sa'o. O le lu'itau autu o lo'o taoto i le liua o in vitro i fa'amaumauga in vivo ma le iloagofie o metabolites maualalo. I le lumanaʻi, o faʻataʻitaʻiga faʻapitoa e pei o organoids e mafai ona faʻaogaina e faʻaleleia atili ai le faʻatuatuaina o suʻesuʻega.

3 Sulfotransferase (SULT)

Sulfotransferase (SULT)o se ituaiga o transferase e faʻamalosia le fesiitaiga o vaega sulfate ma o loʻo aʻafia i le metabolism o mea faʻapitoa (e pei o hormones ma neurotransmitters) ma mea faʻapitoa (e pei o vailaʻau ma mea faʻaleagaina o le siosiomaga). Sulfotransferases e tele lava ina maua i totonu o le cytoplasm ma Golgi apparatus, e aofia ai i le sulfatation o substrates mole laiti (e pei o fualaau faasaina, hormones, neurotransmitters) ma mole lapopoa (e pei o peptides, proteins, lipids, glycosaminoglycans). Sulfotransferases ua fa'ailoa mai e tele ni vaega laiti, e aofia ai SULT1, SULT2, ma SULT4. Le fa'aletonu ole sulfotransferase e mafai ona o'o atu ai ile fa'agaioiina o fualaau fa'asaina, kanesa, fa'aletonu o le endocrine, ma fa'aletonu ole neura.

4 Sulfation / Sulfonation Metabolism

Sulfonation metabolism (lea e ta'ua o le sulfation metabolism) e iai sona sao taua i le lafoaia o fualaau faasaina ma o se faavae taua mo le atinaeina o fualaau faasaina ma le faaaogaina tatau o fualaau faasaina. O le sulfotransferase a le tagata (lea e taʻua o le sulfatase) e iai le tele o mea'ai i totonu o le tino, e masani ona tufatufaina i totoga e pei o le ate, tootoo laiti, fatugaʻo, ma mama. O SULT masani a tagata e aofia aiSULT1A1, SULT1A3, SULT1B1, SULT1C2, maSULT1C4 (siua 1). Mo le tele o substrates, sulfotransferase mediated metabolism e masani ona faʻaalia uiga masani faʻasaina substrate; Ole maualuga ole fa'aogaina ole mea'ai e masani ona fa'aoso ai le fa'aaliga ole enzyme.

Fuafuaga 1 Le tufatufaina ma le faʻaogaina o se vaega SULT superfamily i totonu o le tino o le tagata

5 Fa'aoga Autu ole SULT ile Atina'eina o Fualaau Fa'asaina

5.1 In Vitro Iloiloga ole DDI Fa'avae ile Metabolism

Ole su'esu'ega in vitro ole SULT mediated DDI e masani lava ona fa'atinoina e ala ile fa'ainitaneti filifilia (e pei ole quercetin, DCNP) po'o le fa'aogaina ole enzyme system i le cytoplasm o le ate tagata po'o fa'ata'ita'iga fa'ata'ita'iga o lo'o fa'aalia ai subtypes patino SULT. O mamanu faʻataʻitaʻi e masani ona aofia ai:

Su'esu'ega phenotype metabolic: Fa'atatau le fua o le fa'atupuina o le metabolite sulfated e le LC-MS/MS ma fa'atatau le fua fa'asaina (tau IC50/Ki).

Va'aiga a'afiaga ile falema'i: Afai e fa'aitiitia le gaosiga ole metabolite e le inhibitor (vaega fa'asaina> 50%), e ta'u mai ai e ono fa'alavelave i le fa'amamaina o vaila'au fa'alagolago ile SULT metabolism, ma e mana'omia le fa'amaonia atili i vivo.

5.2 SULT Su'esu'ega Mausali o Metabolic

I le atinaʻeina o vailaʻau, o le suʻesuʻega o le SULT metabolic stability e faia e ala i le incubation in vitro (hepatic cytoplasm / APS) faʻatasi ma le LC - MS / MS suʻesuʻega e fuafua ai le vailaʻau sulfation fua ma le gaosiga o le metabolite, faʻamaonia sao o le SULT subtype autu, iloilo faʻamaʻi faʻamaʻi pipisi, ma taʻitaʻia le optimization fausaga.

5.3 Su'esu'ega Fa'asaienisi Metabolic

Ole metotia su'esu'e ole su'esu'ega (metabolic pathway identification method) ole SULT e mafai ona fa'asino sa'o ile mamanu ole CYP enzymes, lea e fa'aaoga muamua ai vaila'au fa'asaina e su'e ai subtypes talafeagai, ona fa'amaonia lea i gene recombinases ma fuafua lo latou sao.

O le mataupu faavae autu ma le auala faʻapitoa o le suʻega vailaʻau faʻasaina o le SULT o le suʻesuʻeina lea pe faʻafefeina le metabolism o le tina poʻo le gaosiga o le metabolite e ala i le faʻaogaina o le iniseti filifilia Quercetin ma DCNP o le SULT i le tino o le cytoplasm system.

5.4 Su'esu'ega Fa'asaina ole Enzyme

SULT o loʻo aʻafia i le metabolism o le tele o vailaʻau ma vailaʻau. Afai o lo'o fa'atupuina vaila'au e fa'alavelave ai le gaioiga a le SULT, e ono iai ni fa'afitauli saogalemu pe a fa'asoa atu vaila'au. O le mataupu autu ma le auala faʻapitoa ole suʻega ole enzyme inhibition ole SULT ole faʻaogaina ole sult pure enzyme system e iloa ai pe faʻalavelaveina le gaosiga o le metabolite p-nitrophenol sulfate e ala i le faʻaopoopoina o vailaʻau suʻesuʻe ma suʻega suʻega e pei ole p-nitrophenol.

6 Faaiuga

Sulfotransferase (SULT) e iai sona sao taua i le metabolism o fualaau, vailaʻau-fesoʻotaʻiga fualaau (DDI), ma suʻesuʻega saogalemu. O le fa'aogaina o le sulfation metabolism e a'afia ai le kilia o vaila'au, fa'agaoioia, po'o le o'ona (e pei o le metabolism o vaila'au o le homone ma le fa'aleagaina o le si'osi'omaga), a'o su'esu'ega fa'asaina ole enzyme e mafai ona va'ai ai le lamatiaga ole DDI ile falema'i. E ala i le tuʻufaʻatasia o faʻataʻitaʻiga in vitro (cytoplasm ate, enzymes recombinant) faʻatasi ma le LC - MS / MS tekonolosi, o saofaga metabolic o SULT subtypes (e pei o SULT1A1, SULT2A1) e mafai ona faʻamalamalamaina, taʻitaʻia le faʻatulagaina o vailaʻau ma vailaʻau faʻapitoa. I le lumanaʻi, faʻataʻitaʻiga faʻapitoa e pei o organoids o le a faʻaleleia atili ai le tau faʻaliliuga o suʻesuʻega SULT, tuʻuina atu faʻataʻitaʻiga saʻo saʻo mo le mautu ma le saogalemu i le atinaʻeina o fualaau faasaina.

Fa'asinomaga

Li, Y., Lindsay, J., Wang, L. L., & Zhou, S. F. (2008). Fauga, galuega ma polymorphism o tagata cytosolic sulfotransferases. Metabolism fualaau faasaina i le taimi nei, 9(2), 99-105.