Sulfotransferase (SULT) don Binciken DDI, Ƙarfafawar Metabolic, da Inhibition Enzyme

Key kalmomi: miyagun ƙwayoyi

1 IPHASE Yana Haɗuwa

2 Binciken Enzymatic a Ci gaban Drug

A cikin ci gaban miyagun ƙwayoyi, nazarin halittu na rayuwa da hana enzymes na enzymes na rayuwa kamar CYP450, UGT, SULT, da dai sauransu yana da mahimmanci. Binciken metabolic phenotype yana amfani da samfuran in vitro haɗe tare da fasahar LC - fasahar MS/MS don gano manyan hanyoyin rayuwa, mahimman enzymes na rayuwa, da sigogin motsin su (kamar km/Vmax) na magunguna, da kimanta tasirin polymorphism na kwayoyin halitta akan keɓaɓɓen magani. Binciken hanawar Enzyme yana mai da hankali kan tasirin hanawa na kwayoyi ko mahadi akan enzymes na rayuwa (kamar hanawa mai jujjuyawa / wanda ba zai iya jurewa ba), auna ƙimar IC50/Ki don tsinkaya.miyagun ƙwayoyi - hulɗar ƙwayoyi (DDI)kasada. Waɗannan karatun suna ba da tushen kimiyya don haɓaka ƙirar ƙwayoyi, kimanta aminci (kamar gano metabolites masu guba), da jagorantar madaidaicin magani. Babban ƙalubalen ya ta'allaka ne a cikin jujjuyawar in vitro zuwa bayanan in vivo da ƙwarewar gano ƙananan ƙwayoyin metabolites. A nan gaba, ana iya amfani da samfuran ci-gaba irin su organoids don ƙara haɓaka amincin bincike.

3 Sulfotransferase (SULT)

Sulfotransferase (SULT)wani nau'i ne na transferase wanda ke haifar da canja wurin ƙungiyoyin sulfate kuma yana da hannu a cikin metabolism na mahadi na endogenous (irin su hormones da neurotransmitters) da ƙananan mahadi (kamar kwayoyi da gurɓataccen muhalli). Sulfotransferases galibi suna cikin cytoplasm da kayan aikin Golgi, waɗanda ke cikin sulfation na ƙananan ƙwayoyin ƙwayoyin cuta (kamar kwayoyi, hormones, neurotransmitters) da manyan ƙwayoyin cuta (kamar peptides, sunadarai, lipids, glycosaminoglycans). Sulfotransferases have been identified to have multiple subtypes, mainly including SULT1, SULT2, and SULT4. Rashin aiki na sulfotransferase zai iya haifar da rashin lafiyar miyagun ƙwayoyi, ciwon daji, cututtuka na endocrin, da cututtuka na jijiyoyi.

4 Sulfation/Sulfonation Metabolism

Sulfonation metabolism (wanda kuma aka sani da sulfation metabolism) yana taka muhimmiyar rawa a cikin zubar da kwayoyi a cikin vivo kuma yana da mahimmancin tushe don sababbin ci gaban ƙwayoyi da amfani da magungunan asibiti na hankali. Sulfotransferase na mutum (wanda kuma aka sani da sulfatase) yana da nau'i mai yawa a cikin jiki, wanda aka rarraba a cikin gabobin jiki kamar hanta, ƙananan hanji, kodan, da huhu. Jama'a SULTs sun haɗa daSaukewa: SULT1A1, Saukewa: SULT1A3, Saukewa: SULT1B1, Saukewa: SULT1C2, kumaSaukewa: SULT1C4 (Table 1). Ga mafi yawan abubuwan da ake amfani da su, sulfotransferase mediated metabolism sau da yawa yana nuna halayen hanawa na al'ada; Ƙananan matakan maida hankali na substrate yawanci suna haifar da maganganun enzyme.

Tebur 1 Rarraba da aikin babban iyali na SULT a cikin jikin mutum

5 Key Applications na SULT a Ci gaban Drug

5.1 In Vitro Evaluation na DDI Dangane da Metabolism

Ƙimar in vitro na SULT mediated DDI ana yin ta ne ta hanyar masu hana masu zaɓaɓɓu (kamar quercetin, DCNP) ko tsarin enzyme recombinant a cikin cytoplasm na hanta na ɗan adam ko ƙirar tantanin halitta waɗanda ke bayyana takamaiman nau'ikan SULT. Ƙirar gwaji yawanci ya haɗa da:

Metabolic phenotype bincike: Ƙididdige ƙimar ƙarni na sulfated metabolite ta LC-MS/MS kuma ƙididdige ƙimar hanawa (ƙimar IC50/Ki).

Hasashen haɗari na asibiti: Idan mai hanawa ya rage yawan samar da metabolite (ƙididdigar hanawa> 50%), yana nuna cewa zai iya tsoma baki tare da kawar da kwayoyi masu dogara ga SULT metabolism, kuma ana buƙatar ƙarin tabbatarwa a cikin vivo.

5.2 SULT Nazarin Ƙarfafa Jiki

A cikin ci gaban ƙwayoyi, ana gudanar da nazarin kwanciyar hankali na SULT ta hanyar incubation in vitro (hepatic cytoplasm / APS) tare da LC - bincike na MS/MS don ƙayyade ƙimar sulfation na miyagun ƙwayoyi da tsararrun ƙwayoyin cuta, gano mahimmin gudunmawar SULT subtype, kimanta haɗarin kawar da rayuwa, da jagoranci ingantawa.

5.3 Binciken Metabolic Substrate

Hanyar bincike na substrate (hanyar gano hanyar gano hanyar metabolic) na SULT na iya kai tsaye zuwa ƙirar enzymes CYP, wanda da farko yana amfani da hana sinadarai don nunawa ga ƙananan nau'ikan da suka dace, sannan kuma tabbatar da su tare da recombinases na gene kuma yana ƙididdige gudummawar danginsu.

Babban ka'ida da hanyar fasaha na gwajin hana sinadarai na SULT shine don kimanta ko an hana haɓakar ƙwayar mahaifa ko samar da metabolite ta hanyar gyaggyarawa inhibitors Quercetin da DCNP na SULT a cikin tsarin cytoplasm na hanta na ɗan adam.

5.4 Binciken Inhibition Enzyme

SULT yana da hannu a cikin metabolism na abubuwa masu yawa na endogenous da kwayoyi. Idan ana haɓaka magunguna don hana ayyukan SULT, ana iya samun yuwuwar al'amurran tsaro yayin raba magunguna. Babban ka'ida da hanyar fasaha na SULT enzyme inhibition assay shine yin amfani da tsarin enzyme mai tsabta SULT don gano ko an hana samar da metabolite p

6 Kammalawa

Sulfotransferase (SULT) yana taka muhimmiyar rawa a cikin metabolism na miyagun ƙwayoyi, miyagun ƙwayoyi - hulɗar magunguna (DDI), da ƙimar aminci. Metabolism na sulfation wanda ke shiga tsakani ta yana shafar kawar da miyagun ƙwayoyi, kunnawa, ko guba (kamar metabolism na magungunan hormone da gurɓataccen muhalli), yayin da binciken hana enzyme na iya hasashen haɗarin DDI na asibiti. Ta hanyar haɗa nau'ikan in vitro (hanta cytoplasm, recombinant enzymes) tare da fasahar LC - MS/MS, gudummawar rayuwa ta nau'ikan nau'ikan SULT (kamar SULT1A1, SULT2A1) za a iya fayyace, jagorar haɓaka tsarin ƙwayoyi da keɓaɓɓen magani. A nan gaba, samfurori masu tasowa irin su organoids za su kara inganta darajar fassarar SULT bincike, samar da ƙarin ma'auni na kimantawa don kwanciyar hankali na rayuwa da aminci a cikin ci gaban ƙwayoyi.

Magana

Li, Y., Lindsay, J., Wang, L. L., & Zhou, S. F. (2008). Tsarin, aiki da polymorphism na ɗan adam cytosolic sulfotransferases. Magungunan ƙwayoyin cuta na yanzu, 9(2), 99-105.