Sulfotransferase (SULT) rau DDI Kev Tshawb Fawb, Metabolic Stability, thiab Enzyme Inhibition

Cov lus tseem ceeb: tshuaj - tshuaj sib cuam tshuam (DDI), sulfotransferase (SULT), enzyme inhibition, SULT metabolic, metabolic stability, human SULT1A1 enzyme, human SULT1A3 enzyme, human SULT1B1 enzyme, human SULT1C2, human SULT1C4 enzyme, human SULT1E1 enzyme 2A, human SULT1E1 enzyme 2A

1 IPHASE tsim tawm

2 Kev Tshawb Fawb Enzymatic hauv Kev Txhim Kho Tshuaj

Hauv kev tsim tshuaj, kev kawm txog cov tshuaj metabolic phenotypes thiab enzyme inhibition ntawm metabolic enzymes xws li CYP450, UGT, SULT, thiab lwm yam yog qhov tseem ceeb. Kev tshawb fawb txog metabolic phenotype siv hauv vitro qauv ua ke nrog LC - MS / MS thev naus laus zis txhawm rau txheeb xyuas cov txheej txheem metabolic tseem ceeb, cov enzymes tseem ceeb hauv metabolic, thiab lawv cov kinetic tsis (xws li Km / Vmax) ntawm cov tshuaj, thiab ntsuas qhov cuam tshuam ntawm cov noob polymorphism ntawm tus kheej cov tshuaj. Enzyme inhibition kev tshawb fawb tsom mus rau inhibitory teebmeem ntawm cov tshuaj los yog cov tebchaw ntawm metabolic enzymes (xws li reversible / irreversible inhibition), ntsuas IC50 / Ki qhov tseem ceeb los kwv yeesdrug-drug interaction (DDI)pheej hmoo. Cov kev tshawb fawb no muab kev tshawb fawb hauv paus rau kev txhim kho kev tsim tshuaj, tshuaj xyuas kev nyab xeeb (xws li txheeb xyuas cov tshuaj lom metabolites), thiab qhia cov tshuaj precision. Qhov kev sib tw tseem ceeb nyob hauv kev hloov pauv ntawm hauv vitro mus rau hauv vivo cov ntaub ntawv thiab kev tshawb pom rhiab heev ntawm cov metabolites tsawg. Nyob rau hauv lub neej yav tom ntej, cov qauv siab xws li organoids tuaj yeem siv los txhim kho kev tshawb fawb ntxiv.

3 sulfotransferase (SULT)

Sulfotransferase (SULT)yog ib hom kev hloov pauv uas ua rau kev hloov pauv ntawm pawg sulfate thiab koom nrog hauv cov metabolism hauv endogenous tebchaw (xws li cov tshuaj hormones thiab neurotransmitters) thiab exogenous compounds (xws li tshuaj thiab ib puag ncig muaj kuab paug). Sulfotransferases feem ntau yog nyob rau hauv cytoplasm thiab Golgi apparatus, koom nrog sulfation ntawm me me molecule substrates (xws li tshuaj, tshuaj hormones, neurotransmitters) thiab loj molecules (xws li peptides, proteins, lipids, glycosaminoglycans). Sulfotransferases tau raug txheeb xyuas tias muaj ntau hom subtypes, feem ntau suav nrog SULT1, SULT2, thiab SULT4. Kev ua haujlwm tsis zoo ntawm sulfotransferase tuaj yeem ua rau cov tshuaj metabolism tsis zoo, mob qog noj ntshav, endocrine ntshawv siab, thiab mob hlwb.

4 Sulfation / Sulfonation Metabolism

Sulfonation metabolism (tseem hu ua sulfation metabolism) ua lub luag haujlwm tseem ceeb hauv vivo pov tseg cov tshuaj thiab yog lub hauv paus tseem ceeb rau kev txhim kho tshuaj tshiab thiab kev siv tshuaj kho mob zoo. Tib neeg sulfotransferase (tseem hu ua sulfatase) muaj ntau yam substrates hauv lub cev, feem ntau faib rau hauv nruab nrog cev xws li daim siab, hnyuv, ob lub raum, thiab lub ntsws. Tib neeg SULTs suav nrogSIB 1A1, SIB 1A3, SIB 1B1, SIB 1C2, thiabSIB 1C4 (tab 1). Rau feem ntau cov substrates, sulfotransferase mediated metabolism feem ntau nthuav tawm cov yam ntxwv ntawm substrate inhibition; Tsawg substrate concentration theem feem ntau induce enzyme qhia.

Table 1 Kev faib tawm thiab kev ua haujlwm ntawm ib feem SULT superfamily hauv tib neeg lub cev

5 Cov Kev Siv Tseem Ceeb ntawm SULT hauv Kev Txhim Kho Tshuaj

5.1 Hauv Vitro Kev Ntsuas ntawm DDI Raws li Metabolism

Kev ntsuam xyuas hauv vitro ntawm SULT mediated DDI feem ntau yog ua los ntawm kev xaiv inhibitors (xws li quercetin, DCNP) los yog cov enzyme recombinant hauv tib neeg lub siab cytoplasm lossis cell qauv qhia tshwj xeeb SULT subtypes. Kev sim tsim feem ntau suav nrog:

Metabolic phenotype tsom xam: Ntsuas tus nqi ntawm sulfated metabolite tiam los ntawm LC-MS/MS thiab xam tus nqi inhibition (IC50/Ki tus nqi).

Kev soj ntsuam kev pheej hmoo: Yog tias tus inhibitor txo qis metabolite ntau lawm (inhibition tus nqi> 50%), nws qhia tias nws yuav cuam tshuam nrog kev tshem tawm cov tshuaj nyob ntawm SULT metabolism, thiab ntxiv rau hauv vivo validation yog xav tau.

5.2 SULT Metabolic Stability Study

Hauv kev tsim tshuaj, txoj kev tshawb fawb ntawm SULT metabolic stability yog ua los ntawm hauv vitro incubation (hepatic cytoplasm / APS) ua ke nrog LC - MS / MS tsom xam los txiav txim siab tshuaj sulfation tus nqi thiab cov txheej txheem metabolite, txheeb xyuas qhov tseem ceeb ntawm SULT subtype contributions, soj ntsuam cov kev pheej hmoo metabolic clearance, thiab qhia kev txhim kho cov qauv.

5.3 Kev Tshawb Fawb Txog Metabolic Substrate

Txoj kev tshawb fawb substrate (metabolic pathway identification method) ntawm SULT tuaj yeem xa ncaj qha mus rau qhov tsim ntawm CYP enzymes, uas yog thawj zaug siv tshuaj inhibition los tshuaj xyuas cov subtypes uas cuam tshuam, thiab tom qab ntawd txheeb xyuas lawv nrog cov noob recombinases thiab suav lawv cov txheeb ze koom nrog.

Lub hauv paus ntsiab lus tseem ceeb thiab txoj hauv kev ntawm kev sim tshuaj inhibition ntawm SULT yog los soj ntsuam seb leej niam cov metabolism lossis metabolite ntau lawm yog inhibited los ntawm kev hloov kho cov kev xaiv inhibitors Quercetin thiab DCNP ntawm SULT hauv tib neeg lub siab cytoplasm system.

5.4 Enzyme Inhibition Research

SULT koom nrog hauv cov metabolism ntawm ntau yam tshuaj endogenous thiab tshuaj. Yog tias cov tshuaj tau tsim los cuam tshuam cov kev ua ntawm SULT, tej zaum yuav muaj teeb meem kev nyab xeeb thaum sib koom tshuaj. Lub hauv paus ntsiab lus tseem ceeb thiab txoj hauv kev ntawm SULT enzyme inhibition assay yog siv SULT ntshiab enzyme system los xyuas seb puas tsim cov metabolite p-nitrophenol sulfate yog inhibited los ntawm kev ntxiv tshuaj soj ntsuam thiab sojntsuam substrates xws li p-nitrophenol.

6 Kev xaus

Sulfotransferase (SULT) plays lub luag haujlwm tseem ceeb hauv cov tshuaj metabolism, tshuaj siv tshuaj yeeb tshuaj (DDI), thiab kev ntsuas kev nyab xeeb. Lub sulfation metabolism hauv nruab nrab los ntawm nws cuam tshuam rau kev tshem tawm cov tshuaj, ua kom muaj zog, lossis muaj tshuaj lom (xws li cov metabolism hauv cov tshuaj hormones thiab cov pa phem ib puag ncig), thaum cov kev tshawb fawb enzyme inhibition tuaj yeem kwv yees qhov kev pheej hmoo ntawm DDI. Los ntawm kev sib txuas hauv vitro qauv (lub siab cytoplasm, recombinant enzymes) nrog LC - MS / MS thev naus laus zis, cov kev pabcuam metabolic ntawm SULT subtypes (xws li SULT1A1, SULT2A1) tuaj yeem qhia meej, qhia cov qauv tshuaj kho kom zoo thiab kho tus kheej. Nyob rau hauv lub neej yav tom ntej, cov qauv qib siab xws li organoids yuav ntxiv dag zog rau kev txhais lus ntawm SULT kev tshawb fawb, muab cov txheej txheem kev ntsuam xyuas ntau dua rau kev ruaj ntseg metabolic thiab kev nyab xeeb hauv kev tsim tshuaj.

Kev siv

Li, Y., Lindsay, J., Wang, L., & Zhou, S. F. (2008). Cov qauv, kev ua haujlwm thiab polymorphism ntawm tib neeg cytosolic sulfotransferases. Tam sim no cov tshuaj metabolism, 9(2), 99-105.