Sulfotransferase(SULT) no ka noiʻi DDI, Metabolic Stability, a me Enzyme Inhibition

Hua'ōlelo nui: lāʻau - lāʻau pilina (DDI), sulfotransferase (SULT), enzyme inhibition, SULT metabolic, metabolic stability, kanaka SULT1A1 enzyme, kanaka SULT1A3 enzyme, kanaka SULT1B1 enzyme, kanaka SULT1C2, kanaka SULT1C4 enzyme, kanaka SULT1E1 enzyme, kanaka SULT2A1 enzyme, kanaka SULT2A1 enzyme

Hana 1 IPHASE

2 Enzymatic Research in Drug Development

I ka hoʻomohala ʻana i ka lāʻau lapaʻau, ʻo ke aʻo ʻana i nā phenotypes metabolic a me ka inhibition enzyme o nā enzyme metabolic e like me CYP450, UGT, SULT, etc. Ke hoʻohana nei ka noiʻi metabolic phenotype i nā hiʻohiʻona in vitro i hui pū ʻia me ka ʻenehana LC-MS/MS e ʻike i nā ala metabolic koʻikoʻi, nā enzyme metabolic kī, a me kā lākou kinetic parameters (e like me Km/Vmax) o nā lāʻau lapaʻau, a loiloi i ka hopena o ka polymorphism gene i ka lāʻau lapaʻau pilikino. Ke nānā aku nei ka noiʻi ʻana i ka enzyme inhibition i nā hopena pale o nā lāʻau lapaʻau a i ʻole nā pūhui i ka metabolic enzymes (e like me ka reversible/irreversible inhibition), e ana i nā waiwai IC50/Ki e wānana.lāʻau - lāʻau pilina (DDI)pilikia. Hāʻawi kēia mau haʻawina i kumu ʻepekema no ka hoʻolālā ʻana i ka lāʻau lapaʻau, loiloi i ka palekana (e like me ka ʻike ʻana i nā metabolite ʻona), a me ke alakaʻi ʻana i ka lāʻau lapaʻau pololei. Aia ka pilikia nui i ka hoʻololi ʻana o ka in vitro i ka ʻikepili in vivo a me ka ʻike ʻana o nā metabolites haʻahaʻa haʻahaʻa. I ka wā e hiki mai ana, hiki ke hoʻohana ʻia nā hiʻohiʻona kiʻekiʻe e like me nā organoids e hoʻonui hou i ka hilinaʻi noiʻi.

3 Sulfotransferase (SULT)

Sulfotransferase (SULT)he ʻano hoʻololi e hoʻokaʻawale i ka hoʻoili ʻana o nā pūʻulu sulfate a komo i ka metabolism o nā pūhui endogenous (e like me nā hormones a me nā neurotransmitters) a me nā pūhui exogenous (e like me nā lāʻau lapaʻau a me nā mea haumia kaiapuni). Aia ka Sulfotransferases i loko o ka cytoplasm a me Golgi apparatus, i komo i ka sulfation o nā substrates liʻiliʻi liʻiliʻi (e like me nā lāʻau lapaʻau, nā hormones, nā neurotransmitters) a me nā molela nui (e like me peptides, proteins, lipids, glycosaminoglycans). Ua ʻike ʻia nā Sulfotransferases he nui nā ʻano subtypes, ʻo ia hoʻi me SULT1, SULT2, a me SULT4. ʻO ka hana ʻole o ka sulfotransferase hiki ke alakaʻi i ka metabolism lāʻau maʻamau, ke kanesa, nā maʻi endocrine, a me nā maʻi neurological.

4 Sulfation / Sulfonation Metabolism

He kuleana koʻikoʻi ka sulfonation metabolism (i ʻike ʻia ʻo sulfation metabolism) i ka hoʻopau ʻana i nā lāʻau lapaʻau in vivo a he kumu nui ia no ka hoʻomohala ʻana i ka lāʻau hou a me ka hoʻohana lāʻau lapaʻau kūpono. ʻO ka sulfotransferase kanaka (kahi i ʻike ʻia ʻo sulfatase) he ʻano nui o nā substrates i loko o ke kino, i puʻunaue nui ʻia i loko o nā kino e like me ke ake, ka ʻōpū liʻiliʻi, nā puʻupaʻa, a me nā māmā. Loaʻa nā SULT kanaka maʻamauSULT1A1, SULT1A3, SULT1B1, SULT1C2, aSULT1C4 (papa 1). No ka hapa nui o nā substrate, hōʻike pinepine ka sulfotransferase mediated metabolism i nā hiʻohiʻona maʻamau kaohi ʻana o ka substrate; ʻO ka haʻahaʻa haʻahaʻa haʻahaʻa haʻahaʻa substrate maʻamau e hoʻoulu i ka hōʻike enzyme.

Papa 1 Ka mahele a me ka hana o ka hapa nui SULT superfamily i loko o ke kino kanaka

5 Nā noi nui o ka SULT i ka hoʻomohala ʻana i nā lāʻau lapaʻau

5.1 In Vitro Evaluation of DDI Ma muli o ka Metabolism

Hoʻokō nui ʻia ka loiloi in vitro o SULT mediated DDI ma o nā mea paʻa koho (e like me quercetin, DCNP) a i ʻole nā ​​ʻōnaehana enzyme recombinant i loko o ka cytoplasm hepatic kanaka a i ʻole nā ​​​​model cell e hōʻike ana i nā subtype SULT kikoʻī. Hoʻokomo pinepine ʻia ka hoʻolālā hoʻokolohua:

ʻIkepili phenotype metabolic: E helu i ka nui o ka hana ʻana o ka metabolite sulfated e LC-MS/MS a e helu i ka helu hoʻokae (waiwai IC50/Ki).

ʻO ka wānana pilikia o ke kino: Inā hoʻemi nui ka mea paʻa i ka hana metabolite (ka inhibition rate> 50%), hōʻike ia e hiki ke hoʻopilikia i ka hoʻomaʻemaʻe ʻana o nā lāʻau i hilinaʻi ʻia i ka metabolism SULT, a pono hou ka hōʻoia in vivo.

5.2 Haʻawina Hoʻopaʻa Metabolic SULT

I ka hoʻomohala ʻana i ka lāʻau lapaʻau, mālama ʻia ke aʻo ʻana o ka SULT metabolic stability ma o in vitro incubation (hepatic cytoplasm/APS) i hui pū ʻia me LC-MS/MS analysis e hoʻoholo ai i ka lāʻau sulfation rate a me ka hanauna metabolite, e ʻike i nā hāʻawi subtype SULT kī, loiloi i nā pilikia hoʻomaʻemaʻe metabolic, a alakaʻi i ka optimization structural.

5.3 Noiʻi Metabolic substrate

Hiki i ke ʻano noiʻi substrate (metabolic pathway identification method) o SULT ke kuhikuhi pololei i ka hoʻolālā ʻana o nā enzymes CYP, ka mea e hoʻohana mua i ka pale kemika no ka nānā ʻana no nā subtypes kūpono, a laila hōʻoia iā lākou me nā gene recombinases a helu i kā lākou hāʻawi pili.

ʻO ke kumu nui a me ke ala ʻenehana o ka hoʻāʻo inhibition kemika o SULT ʻo ia ka loiloi ʻana inā pale ʻia ka metabolism o ka makuahine a i ʻole ka hana metabolite e ka hoʻololi ʻana i nā mea koho koho Quercetin a me DCNP o SULT i ka ʻōnaehana cytoplasm hepatic kanaka.

5.4 Ka noiʻi hoʻopaʻa ʻana i ka enzyme

Hoʻopili ʻo SULT i ka metabolism o nā mea endogenous a me nā lāʻau lapaʻau. Inā hoʻomohala ʻia nā lāʻau lapaʻau e kāohi i ka hana a SULT, aia paha nā pilikia palekana i ka wā e kaʻana like ʻana i nā lāʻau lapaʻau. ʻO ke kumu nui a me ke ala ʻenehana o ka SULT enzyme inhibition assay, ʻo ia ka hoʻohana ʻana i kahi ʻōnaehana enzyme maʻemaʻe SULT no ka ʻike ʻana inā ke kāohi ʻia ka hana ʻana o ka metabolite p-nitrophenol sulfate ma o ka hoʻohui ʻana i nā lāʻau noiʻi a me nā substrates probe e like me p-nitrophenol.

6 Ka hopena

He kuleana koʻikoʻi ʻo Sulfotransferase (SULT) i ka metabolism lāʻau, lāʻau - lāʻau pilina (DDI), a me ka loiloi palekana. Hoʻopili ka sulfation metabolism i ka hoʻomaʻemaʻe ʻana i ka lāʻau, hoʻōla, a i ʻole nā ​​​​mea ʻawaʻawa (e like me ka metabolism o nā lāʻau lapaʻau hormone a me nā mea hoʻohaumia kaiapuni), ʻoiai nā haʻawina inhibition enzyme hiki ke wānana i ka pilikia DDI maʻi. Ma ka hoʻohui ʻana i nā hiʻohiʻona in vitro (cytoplasm ate, recombinant enzymes) me ka ʻenehana LC-MS/MS, hiki ke wehewehe ʻia nā haʻawina metabolic o nā subtype SULT (e like me SULT1A1, SULT2A1), e alakaʻi ana i ka hoʻoponopono ʻana i ka lāʻau lapaʻau a me ka lāʻau lapaʻau pilikino. I ka wā e hiki mai ana, e hoʻonui hou ʻia nā kumu hoʻohālike kiʻekiʻe e like me nā organoids i ka waiwai unuhi o ka noiʻi SULT, e hāʻawi ana i nā kumu loiloi loiloi kūpono no ka paʻa o ka metabolic a me ka palekana i ka hoʻomohala ʻana i ka lāʻau.

Kuhikuhi

Li, Y., Lindsay, J., Wang, L. L., & Zhou, S. F. (2008). ʻO ke ʻano, ka hana a me ka polymorphism o nā cytosolic sulfotransferases kanaka. ʻO ka metabolism lāʻau i kēia manawa, 9(2), 99-105.