Sulfotransferase(SULT) ya DDI Research, Metabolic Stability, and Enzyme Inhibition

Mawu ofunikira: mankhwala-kulumikizana kwamankhwala (DDI), sulfotransferase (SULT), kuletsa kwa enzyme, SULT metabolic, kukhazikika kwa metabolic, enzyme yamunthu SULT1A1, enzyme yamunthu SULT1A3, enzyme yamunthu SULT1B1, SULT1C2 yamunthu, SULT1C4 enzyme, munthu SULT111E2 enzyme

1 IPHASE Imapanga

2 Kafukufuku wa Enzymatic mu Kupititsa patsogolo Mankhwala

Pakukula kwa mankhwala, kuphunzira kwa metabolic phenotypes ndi kuletsa kwa ma enzymes a metabolic enzymes monga CYP450, UGT, SULT, etc. Kafukufuku wa metabolic phenotype amagwiritsa ntchito mitundu ya in vitro yophatikizidwa ndi ukadaulo wa LC-MS/MS kuti azindikire njira zazikulu za kagayidwe kachakudya, ma enzyme ofunikira a metabolic, ndi magawo awo a kinetic (monga Km/Vmax) yamankhwala, ndikuwunika momwe jini ya polymorphism imakhudzira munthu payekha. Kafukufuku woletsa ma enzyme amayang'ana kwambiri za kulepheretsa kwa mankhwala kapena mankhwala ophatikizika pazagayidwe kagayidwe kazinthu (monga zoletsa zosinthika / zosasinthika), kuyeza milingo ya IC50/Ki kulosera.mankhwala-kuyanjana kwamankhwala (DDI)chiopsezo. Maphunzirowa amapereka maziko asayansi okometsera kamangidwe ka mankhwala, kuwunika chitetezo (monga kuzindikira ma metabolites oopsa), ndi kuwongolera mankhwala olondola. Vuto lalikulu lagona pakusintha kwa in vitro kukhala mu vivo data komanso kuzindikira kwa ma metabolites otsika kwambiri. M'tsogolomu, zitsanzo zapamwamba monga ma organoids zitha kugwiritsidwa ntchito kupititsa patsogolo kudalirika kwa kafukufuku.

3 Sulfotransferase (SULT)

Sulfotransferase (SULT)ndi mtundu wa transferase umene umayambitsa kusamutsidwa kwa magulu a sulfate ndipo umakhudzidwa ndi kagayidwe kameneka kamene kamakhalapo (monga mahomoni ndi ma neurotransmitters) ndi mankhwala akunja (monga mankhwala osokoneza bongo ndi zowononga chilengedwe). Sulfotransferases makamaka ili mu cytoplasm ndi Golgi zida, nawo sulfation wa magawo ang'onoang'ono molekyulu (monga mankhwala, mahomoni, neurotransmitters) ndi mamolekyu aakulu (monga peptides, mapuloteni, lipids, glycosaminoglycans). Sulfotransferases adziwika kuti ali ndi mitundu ingapo, makamaka SULT1, SULT2, ndi SULT4. Kulephera kugwira ntchito kwa sulfotransferase kungayambitse kusokonezeka kwa kagayidwe ka mankhwala, khansa, matenda a endocrine, ndi matenda a ubongo.

4 Sulfation/Sulfation Metabolism

Sulfation metabolism (yomwe imadziwikanso kuti sulfation metabolism) imakhala ndi gawo lofunikira pakutaya kwamankhwala mu vivo ndipo ndi maziko ofunikira pakupanga mankhwala atsopano komanso kugwiritsa ntchito bwino mankhwala osokoneza bongo. Sulfotransferase yaumunthu (yomwe imadziwikanso kuti sulfatase) ili ndi magawo ambiri m'thupi, makamaka omwe amagawidwa m'zigawo monga chiwindi, matumbo aang'ono, impso, ndi mapapo. SULTs wamba wa anthu akuphatikizapoChithunzi cha SULT1A1, SULT1A3, Chithunzi cha SULT1B1, Chithunzi cha SULT1C2,ndiMtengo wa SULT1C4 (tebulo 1). Kwa magawo ambiri, sulfotransferase mediated metabolism nthawi zambiri amawonetsa mawonekedwe oletsa gawo lapansi; Miyezo yotsika ya gawo lapansi nthawi zambiri imapangitsa kuti ma enzyme awoneke.

Table 1 Kugawa ndi ntchito ya gawo lalikulu la SULT m'thupi la munthu

5 Ntchito Zofunika Kwambiri za SULT mu Kupititsa patsogolo Mankhwala Osokoneza Bongo

5.1 In Vitro Kuwunika kwa DDI Kutengera Metabolism

Kuwunika kwa in vitro kwa SULT mediated DDI kumachitika makamaka kudzera mu zoletsa zosankhidwa (monga quercetin, DCNP) kapena ma enzyme ophatikizanso mu cytoplasm yachiwindi yamunthu kapena ma cell omwe amawonetsa ma SULT subtypes. Mapangidwe oyesera amakhala ndi:

Kusanthula kwa metabolic phenotype: Kuwerengera kuchuluka kwa sulphate metabolite generation ndi LC-MS/MS ndi kuwerengera mlingo woletsa (IC50/Ki value).

Kuneneratu kwachiwopsezo chachipatala: Ngati inhibitor imachepetsa kwambiri kupanga metabolite (kuletsa kuchuluka kwa 50%), zikuwonetsa kuti zitha kusokoneza chilolezo chamankhwala omwe amadalira kagayidwe ka SULT, komanso kutsimikizika kwa vivo kumafunika.

Phunziro la 5.2 SULT Metabolic Stability Study

Pachitukuko cha mankhwala, kafukufuku wa kukhazikika kwa SULT kagayidwe kachakudya amachitidwa kudzera mu in vitro incubation (hepatic cytoplasm/APS) pamodzi ndi LC-MS/MS kusanthula kuti mudziwe mlingo wa sulfation sulfation ndi metabolite generation, kuzindikira zopereka zazikulu za SULT subtype, kuyesa kuopsa kwa metabolic clearance, ndi kutsogolera kukhathamiritsa kwapangidwe.

5.3 Kafukufuku wa Metabolic Substrate

Njira yofufuzira gawo lapansi (njira yozindikiritsa njira ya metabolic) ya SULT ingatanthauze mwachindunji mapangidwe a ma enzymes a CYP, omwe poyamba amagwiritsa ntchito kuletsa kwamankhwala kuti awonere ma subtypes ofunikira, kenako amawatsimikizira ndi ma gene recombinases ndikuwerengera gawo lawo.

Mfundo yaikulu ndi njira yaukadaulo ya mayeso oletsa kuletsa kwamankhwala a SULT ndikuwunika ngati kagayidwe kazakudya kapena kupanga metabolite kumalepheretsedwa mwa kusintha zoletsa zosankhidwa Quercetin ndi DCNP za SULT mu dongosolo la hepatic cytoplasm.

Kafukufuku wa 5.4 Enzyme Inhibition Research

SULT imakhudzidwa ndi kagayidwe kazinthu zingapo zamkati ndi mankhwala. Ngati mankhwala akupangidwa kuti aletse ntchito ya SULT, pakhoza kukhala zovuta zachitetezo pogawana mankhwala. Mfundo yaikulu ndi njira yaukadaulo ya SULT enzyme inhibition assay ndiyo kugwiritsa ntchito SULT pure enzyme system kuti azindikire ngati kupanga metabolite p-nitrophenol sulfate kumalephereka powonjezera mankhwala ofufuza ndi magawo a probe monga p-nitrophenol.

6 Mapeto

Sulfotransferase (SULT) imagwira ntchito yofunika kwambiri pakupanga kagayidwe kazamankhwala, mankhwala-kuyanjana kwamankhwala (DDI), komanso kuunika kwachitetezo. Kuphatikizika kwa sulfation komwe kumalumikizidwa ndi izi kumakhudza kuchotsedwa kwa mankhwala, kuyambitsa, kapena kawopsedwe (monga kagayidwe ka mankhwala a mahomoni ndi zoipitsa zachilengedwe), pomwe maphunziro oletsa ma enzyme amatha kulosera za ngozi ya DDI. Pophatikiza mitundu ya in vitro (chiwindi cha cytoplasm, ma enzymes ophatikizana) ndi ukadaulo wa LC - MS/MS, zopereka za metabolic za SULT subtypes (monga SULT1A1, SULT2A1) zitha kumveka bwino, kutsogolera kukhathamiritsa kwa kapangidwe ka mankhwala ndi mankhwala omwe amadzipangira okha. M'tsogolomu, zitsanzo zapamwamba monga ma organoids zidzapititsa patsogolo phindu lomasulira la kafukufuku wa SULT, ndikupereka njira zowunikira zowonetsera kukhazikika kwa metabolic ndi chitetezo pa chitukuko cha mankhwala.

Buku

Li, Y., Lindsay, J., Wang, L. L., & Zhou, S. F. (2008). Kapangidwe, ntchito ndi polymorphism ya anthu cytosolic sulfotransferases. Panopa mankhwala kagayidwe, 9(2), 99 - 105.