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Stereoselective Oxidation Kinetics of Deoxycholate in Recombinant and Microsomal CYP3A Enzymes: Deoxycholate 19-Hydroxylation Is an In Vitro Marker of CYP3A7 Activity.
Chen, Yu-Jie; Zhang, Jian; Zhu, Ping-Ping; Tan, Xian-Wen; Lin, Qiu-Hong; Wang, Wen-Xia; Yin, Shan-Shan; Gao, Ling-Zhi; Su, Ming-Ming; Liu, Chang-Xiao; Xu, Liang; Jia, Wei; Sevrioukova, Irina F; Lan, Ke.
  • Chen YJ; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China (Y.-J.C., J.Z., P.-P.Z., X.-W.T., Q.-H.L., W.W., S.-S.Y., L.-Z.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawa
  • Zhang J; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China (Y.-J.C., J.Z., P.-P.Z., X.-W.T., Q.-H.L., W.W., S.-S.Y., L.-Z.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawa
  • Zhu PP; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China (Y.-J.C., J.Z., P.-P.Z., X.-W.T., Q.-H.L., W.W., S.-S.Y., L.-Z.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawa
  • Tan XW; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China (Y.-J.C., J.Z., P.-P.Z., X.-W.T., Q.-H.L., W.W., S.-S.Y., L.-Z.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawa
  • Lin QH; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China (Y.-J.C., J.Z., P.-P.Z., X.-W.T., Q.-H.L., W.W., S.-S.Y., L.-Z.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawa
  • Wang WX; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China (Y.-J.C., J.Z., P.-P.Z., X.-W.T., Q.-H.L., W.W., S.-S.Y., L.-Z.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawa
  • Yin SS; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China (Y.-J.C., J.Z., P.-P.Z., X.-W.T., Q.-H.L., W.W., S.-S.Y., L.-Z.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawa
  • Gao LZ; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China (Y.-J.C., J.Z., P.-P.Z., X.-W.T., Q.-H.L., W.W., S.-S.Y., L.-Z.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawa
  • Su MM; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China (Y.-J.C., J.Z., P.-P.Z., X.-W.T., Q.-H.L., W.W., S.-S.Y., L.-Z.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawa
  • Liu CX; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China (Y.-J.C., J.Z., P.-P.Z., X.-W.T., Q.-H.L., W.W., S.-S.Y., L.-Z.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawa
  • Xu L; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China (Y.-J.C., J.Z., P.-P.Z., X.-W.T., Q.-H.L., W.W., S.-S.Y., L.-Z.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawa
  • Jia W; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China (Y.-J.C., J.Z., P.-P.Z., X.-W.T., Q.-H.L., W.W., S.-S.Y., L.-Z.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawa
  • Sevrioukova IF; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China (Y.-J.C., J.Z., P.-P.Z., X.-W.T., Q.-H.L., W.W., S.-S.Y., L.-Z.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawa
  • Lan K; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China (Y.-J.C., J.Z., P.-P.Z., X.-W.T., Q.-H.L., W.W., S.-S.Y., L.-Z.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawa
Drug Metab Dispos ; 47(6): 574-581, 2019 06.
Article en En | MEDLINE | ID: mdl-30918015
ABSTRACT
The primary bile acids (BAs) synthesized from cholesterol in the liver are converted to secondary BAs by gut microbiota. It was recently disclosed that the major secondary BA, deoxycholate (DCA) species, is stereoselectively oxidized to tertiary BAs exclusively by CYP3A enzymes. This work subsequently investigated the in vitro oxidation kinetics of DCA at C-1ß, C-3ß, C-4ß, C-5ß, C-6α, C-6ß, and C-19 in recombinant CYP3A enzymes and naive enzymes in human liver microsomes (HLMs). The stereoselective oxidation of DCA fit well with Hill kinetics at 1-300 µM in both recombinant CYP3A enzymes and pooled HLMs. With no contributions or trace contributions from CYP3A5, CYP3A7 favors oxidation at C-19, C-4ß, C-6α, C-3ß, and C-1ß, whereas CYP3A4 favors the oxidation at C-5ß and C-6ß compared with each other. Correlation between DCA oxidation and testosterone 6ß-hydroxylation in 14 adult single-donor HLMs provided proof-of-concept evidence that DCA 19-hydroxylation is an in vitro marker reaction for CYP3A7 activity, whereas oxidation at other sites represents mixed indicators for CYP3A4 and CYP3A7 activities. Deactivation caused by DCA-induced cytochrome P450-cytochrome P420 conversion, as shown by the spectral titrations of isolated CYP3A proteins, was observed when DCA levels were near or higher than the critical micelle concentration (about 1500 µM). Unlike CYP3A4, CYP3A7 showed abnormally elevated activities at 500 and 750 µM, which might be associated with an altered affinity for DCA multimers. The disclosed kinetic and functional roles of CYP3A isoforms in disposing of the gut bacteria-derived DCA may help in understanding the structural and functional mechanisms of CYP3A.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Biomarcadores / Ácido Desoxicólico / Citocromo P-450 CYP3A Límite: Humans Idioma: En Año: 2019 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Biomarcadores / Ácido Desoxicólico / Citocromo P-450 CYP3A Límite: Humans Idioma: En Año: 2019 Tipo del documento: Article