Sulfotransferase(SULT) bakeng sa Patlisiso ea DDI, Botsitso ba Metabolic, le Thibelo ea Enzyme

Mantsoe a bohlokoa: lithethefatsi-tšebelisano ea lithethefatsi (DDI), sulfotransferase (SULT), thibelo ea enzyme, SULT metabolism, botsitso ba metabolism, enzyme ea motho SULT1A1, enzyme ea motho SULT1A3, enzyme ea motho SULT1B1, SULT1C2 ea motho, enzyme ea motho SULT1C4 SULT1 enzyme ea motho, enzyme ea motho SULT1E2

1 IPHASE E Hlahisa

2 Lipatlisiso tsa Enzymatic ho Tsoelo-pele ea Lithethefatsi

Ho nts'etsopele ea lithethefatsi, thuto ea metabolic phenotypes le inhibition ea enzyme ea li-enzyme tsa metabolic tse kang CYP450, UGT, SULT, joalo-joalo e bohlokoa. Patlisiso ea phenotype ea metabolic e sebelisa mefuta ea in vitro e kopantsoeng le theknoloji ea LC-MS/MS ho khetholla litsela tse kholo tsa metabolism, li-enzyme tsa bohlokoa tsa metabolic, le li-parameter tsa tsona tsa kinetic (tse kang Km/Vmax) ea lithethefatsi, le ho lekola phello ea liphatsa tsa lefutso tsa polymorphism meriana e ikhethileng. Patlisiso ea thibelo ea enzyme e shebana le litlamorao tsa lithibela-mafu tsa lithethefatsi kapa metsoako ho li-enzyme tsa metabolism (joalo ka thibelo e ka khutlisang / e ke keng ea fetoloa), ho lekanya boleng ba IC50/Ki ho bolela esale pele.tšebelisano ea lithethefatsi - lithethefatsi (DDI)kotsi. Lithuto tsena li fana ka motheo oa mahlale oa ho ntlafatsa moralo oa lithethefatsi, ho lekola polokeho (joalo ka ho tseba metabolite e chefo), le ho fana ka meriana e nepahetseng. Phephetso ea mantlha e mabapi le phetoho ea in vitro ho data ea in vivo le kutloelo-bohloko ea ho lemoha ha metabolite e tlase haholo. Nakong e tlang, mefuta e tsoetseng pele joalo ka li-organoid e ka sebelisoa ho ntlafatsa ts'epahalo ea lipatlisiso.

3 Sulfotransferase (SULT)

Sulfotransferase (SULT)ke mofuta oa phetisetso o hlohlelletsang phetiso ea lihlopha tsa sulfate 'me o ameha metabolism ea metsoako ea endogenous (joalo ka lihomone le li-neurotransmitters) le metsoako ea kantle (joalo ka lithethefatsi le litšila tsa tikoloho). Li-sulfotransferase li fumaneha haholo ho cytoplasm le lisebelisoa tsa Golgi, tse amehang ho sulfation ea likaroloana tse nyane tsa molek'hule (joalo ka lithethefatsi, lihormone, li-neurotransmitters) le limolek'hule tse kholo (joalo ka li-peptide, liprotheine, lipids, glycosaminoglycans). Li-sulfotransferase li fumanoe li na le li-subtypes tse ngata, haholo-holo tse kenyelletsang SULT1, SULT2, le SULT4. Ho se sebetse hantle ha sulfotransferase ho ka lebisa ho metabolism e sa tloaelehang ea lithethefatsi, mofets'e, mathata a endocrine, le mathata a methapo.

4 Sulfation/Sulfation Metabolism

Sulfation metabolism (eo hape e tsejoang e le sulfation metabolism) e phetha karolo ea bohlokoa tabeng ea ho lahlela lithethefatsi ka har'a vivo 'me ke motheo oa bohlokoa bakeng sa nts'etsopele ea lithethefatsi tse ncha le tšebeliso e utloahalang ea lithethefatsi. Human sulfotransferase (eo hape e tsejoang e le sulfatase) e na le likaroloana tse ngata tse ngata 'meleng, haholo-holo tse ajoang lithong tse kang sebete, mala a manyane, liphio le matšoafo. Li-SULT tse tloaelehileng tsa batho li kenyelletsaSULT1A1, SULT1A3, SULT1B1, SULT1C2, leSULT1C4 (tafole 1). Bakeng sa li-substrates tse ngata, sulfotransferase mediated metabolism hangata e bontša litšobotsi tse tloaelehileng tsa ho thibela substrate; Maemo a tlase a substrate hangata a baka tlhahiso ea enzyme.

Letlapa la 1 Kabo le ts'ebetso ea karolo e itseng ea SULT superfamily 'meleng oa motho

Likopo tsa 5 tsa bohlokoa tsa SULT ho nts'etsopele ea lithethefatsi

5.1 Tlhahlobo ea In Vitro ea DDI e Thehiloe ho Metabolism

Tlhahlobo ea in vitro ea SULT mediated DDI e etsoa haholo-holo ka li-inhibitors tse khethiloeng (tse kang quercetin, DCNP) kapa mekhoa ea li-enzyme ea recombinant ho cytoplasm ea hepatic ea motho kapa mefuta ea lisele e hlalosang mefuta e itseng ea SULT. Moralo oa liteko hangata o kenyelletsa:

Tlhahlobo ea metabolic phenotype: Lekanya sekhahla sa tlhahiso ea sulfate metabolite ka LC-MS/MS 'me u bale sekhahla sa ho thibela (boleng ba IC50/Ki).

Tlhaloso ea kotsi ea meriana: Haeba inhibitor e fokotsa haholo tlhahiso ea metabolite (tekanyo ea ho thibela ho feta> 50%), e fana ka maikutlo a hore e ka kena-kenana le ho tlosoa ha lithethefatsi tse itšetlehileng ka metabolism ea SULT, 'me ho feta moo ho hlokahala hore ho netefatsoe ka vivo.

5.2 Thuto ea SULT Metabolic Stability

Ho nts'etsopele ea lithethefatsi, thuto ea SULT metabolic stability e etsoa ka in vitro incubation (hepatic cytoplasm/APS) e kopantsoeng le LC - MS/MS analysis ho fumana tekanyo ea sulfation ea lithethefatsi le moloko oa metabolite, ho khetholla menehelo ea bohlokoa ea SULT, ho lekola likotsi tsa ho tlosoa ha metabolism, le ho tataisa ntlafatso ea moralo.

5.3 Lipatlisiso tsa Metabolic Substrate

Mokhoa oa ho etsa lipatlisiso ka substrate (metabolism pathway identification method) oa SULT o ka bua ka ho toba ho moralo oa li-enzyme tsa CYP, tse sebelisang pele ho thibela lik'hemik'hale ho shebella li-subtypes tse amehang, ebe li li netefatsa ka liphatsa tsa lefutso le ho bala monehelo oa tsona o lekanyelitsoeng.

Molao-motheo o ka sehloohong le mokhoa oa theknoloji oa teko ea ho thibela lik'hemik'hale tsa SULT ke ho hlahloba hore na metabolism ea 'mè kapa tlhahiso ea metabolite e thibetsoe ka ho fetola li-inhibitors tse khethiloeng Quercetin le DCNP ea SULT tsamaisong ea cytoplasm ea motho.

5.4 Lipatlisiso tsa Thibelo ea Li-Enzyme

SULT e ameha metabolism ea lintho tse ngata tse sa feleng le lithethefatsi. Haeba lithethefatsi li ntse li etsoa ho thibela ts'ebetso ea SULT, ho ka 'na ha e-ba le mathata a tšireletso ha u arolelana lithethefatsi. Molao-motheo o ka sehloohong le tsela ea theknoloji ea SULT enzyme inhibition assay ke ho sebelisa SULT pure enzyme system ho fumana hore na tlhahiso ea metabolite p-nitrophenol sulfate e thibetsoe ka ho eketsa lithethefatsi tsa lipatlisiso le li-probe substrates tse kang p-nitrophenol.

6 Qetello

Sulfotransferase (SULT) e bapala karolo ea bohlokoa ho metabolism ea lithethefatsi, lithethefatsi-tšebelisano ea lithethefatsi (DDI), le tlhahlobo ea polokeho. Sulfation metabolism e kenelletseng ke eona e ama ho tlosoa ha lithethefatsi, ho kenya tšebetsong, kapa chefo (joalo ka metabolism ea lithethefatsi tsa lihormone le litšila tsa tikoloho), athe lithuto tsa thibelo ea enzyme li ka bolela esale pele kotsi ea DDI. Ka ho kopanya mefuta ea li-in vitro (cytoplasm ea sebete, li-enzyme tse tsosolosang) le theknoloji ea LC - MS/MS, menehelo ea metabolic ea SULT subtypes (e kang SULT1A1, SULT2A1) e ka hlakisoa, e tataisang ntlafatso ea sebopeho sa lithethefatsi le meriana ea motho ka mong. Nakong e tlang, mehlala e tsoetseng pele e kang li-organoids e tla tsoela pele ho ntlafatsa boleng ba phetolelo ea lipatlisiso tsa SULT, ho fana ka litekanyetso tse nepahetseng tsa tlhahlobo bakeng sa botsitso ba metabolism le polokeho ntlafatsong ea lithethefatsi.

Referense

Li, Y., Lindsay, J., Wang, L. L., & Zhou, S. F. (2008). Sebopeho, mosebetsi le polymorphism ea batho ba cytosolic sulfotransferase. Metabolism ea hona joale ea lithethefatsi, 9(2), 99-105.