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Metabolomic and transcriptomic analysis reveals endogenous substrates and metabolic adaptation in rats lacking Abcg2 and Abcb1a transporters.
Ganguly, Samit; Finkelstein, David; Shaw, Timothy I; Michalek, Ryan D; Zorn, Kimberly M; Ekins, Sean; Yasuda, Kazuto; Fukuda, Yu; Schuetz, John D; Mukherjee, Kamalika; Schuetz, Erin G.
Afiliação
  • Ganguly S; Cancer & Developmental Biology Track, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
  • Finkelstein D; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
  • Shaw TI; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
  • Michalek RD; Metabolon Inc, Durham, North Carolina, United States of America.
  • Zorn KM; Collaborations Pharmaceuticals, Inc., Raleigh, North Carolina, United States of America.
  • Ekins S; Collaborations Pharmaceuticals, Inc., Raleigh, North Carolina, United States of America.
  • Yasuda K; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
  • Fukuda Y; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
  • Schuetz JD; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
  • Mukherjee K; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
  • Schuetz EG; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
PLoS One ; 16(7): e0253852, 2021.
Article em En | MEDLINE | ID: mdl-34255797
Abcg2/Bcrp and Abcb1a/Pgp are xenobiotic efflux transporters limiting substrate permeability in the gastrointestinal system and brain, and increasing renal and hepatic drug clearance. The systemic impact of Bcrp and Pgp ablation on metabolic homeostasis of endogenous substrates is incompletely understood. We performed untargeted metabolomics of cerebrospinal fluid (CSF) and plasma, transcriptomics of brain, liver and kidney from male Sprague Dawley rats (WT) and Bcrp/Pgp double knock-out (dKO) rats, and integrated metabolomic/transcriptomic analysis to identify putative substrates and perturbations in canonical metabolic pathways. A predictive Bayesian machine learning model was used to predict in silico those metabolites with greater substrate-like features for either transporters. The CSF and plasma levels of 169 metabolites, nutrients, signaling molecules, antioxidants and lipids were significantly altered in dKO rats, compared to WT rats. These metabolite changes suggested alterations in histidine, branched chain amino acid, purine and pyrimidine metabolism in the dKO rats. Levels of methylated and sulfated metabolites and some primary bile acids were increased in dKO CSF or plasma. Elevated uric acid levels appeared to be a primary driver of changes in purine and pyrimidine biosynthesis. Alterations in Bcrp/Pgp dKO CSF levels of antioxidants, precursors of neurotransmitters, and uric acid suggests the transporters may contribute to the regulation of a healthy central nervous system in rats. Microbiome-generated metabolites were found to be elevated in dKO rat plasma and CSF. The altered dKO metabolome appeared to cause compensatory transcriptional change in urate biosynthesis and response to lipopolysaccharide in brain, oxidation-reduction processes and response to oxidative stress and porphyrin biosynthesis in kidney, and circadian rhythm genes in liver. These findings present insight into endogenous functions of Bcrp and Pgp, the impact that transporter substrates, inhibitors or polymorphisms may have on metabolism, how transporter inhibition could rewire drug sensitivity indirectly through metabolic changes, and identify functional Bcrp biomarkers.
Assuntos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Subfamília B de Transportador de Cassetes de Ligação de ATP / Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: PLoS One Assunto da revista: CIENCIA / MEDICINA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Subfamília B de Transportador de Cassetes de Ligação de ATP / Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: PLoS One Assunto da revista: CIENCIA / MEDICINA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos