Dataset Information

In Vitro Metabolism Study of Seongsanamide A in Human Liver Microsomes Using Non-Targeted Metabolomics and Feature-Based Molecular Networking.

ABSTRACT: Seongsanamide A is a bicyclic peptide with an isodityrosine residue discovered in Bacillus safensis KCTC 12796BP which exhibits anti-allergic activity in vitro and in vivo without significant cytotoxicity. The purpose of this study was to elucidate the in vitro metabolic pathway and potential for drug interactions of seongsanamide A in human liver microsomes using non-targeted metabolomics and feature-based molecular networking (FBMN) techniques. We identified four metabolites, and their structures were elucidated by interpretation of high-resolution tandem mass spectra. The primary metabolic pathway associated with seongsanamide A metabolism was hydroxylation and oxidative hydrolysis. A reaction phenotyping study was also performed using recombinant cytochrome P450 isoforms. CYP3A4 and CYP3A5 were identified as the major metabolic enzymes responsible for metabolite formation. Seongsanamide A did not inhibit the cytochrome P450 isoforms commonly involved in drug metabolism (IC50 > 10 µM). These results will contribute to further understanding the metabolism and drug interaction potential of various bicyclic peptides.

SUBMITTER: Wu Z

PROVIDER: S-EPMC8309059 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

In Vitro Metabolism Study of Seongsanamide A in Human Liver Microsomes Using Non-Targeted Metabolomics and Feature-Based Molecular Networking.

Wu Zhexue Z Kim Geum Jin GJ Park So-Young SY Shon Jong Cheol JC Liu Kwang-Hyeon KH Choi Hyukjae H

Pharmaceutics 20210707 7

Seongsanamide A is a bicyclic peptide with an isodityrosine residue discovered in <i>Bacillus safensis</i> KCTC 12796BP which exhibits anti-allergic activity in vitro and in vivo without significant cytotoxicity. The purpose of this study was to elucidate the in vitro metabolic pathway and potential for drug interactions of seongsanamide A in human liver microsomes using non-targeted metabolomics and feature-based molecular networking (FBMN) techniques. We identified four metabolites, and their ...[more]

PMID: 34371722

Similar Datasets

Project description:Chemicals often require metabolic activation to become genotoxic. Established test guidelines recommend the use of the rat liver S9 fraction or microsomes to introduce metabolic competence to in vitro cell-based bioassays, but the use of animal-derived components in cell culture raises ethical concerns and may lead to quality issues and reproducibility problems. The aim of the present study was to compare the metabolic activation of cyclophosphamide (CPA) and benzo[a]pyrene (BaP) by induced rat liver microsomes and an abiotic cytochrome P450 (CYP) enzyme based on a biomimetic porphyrine catalyst. For the detection of genotoxic effects, the chemicals were tested in a reporter gene assay targeting the activation of the cellular tumor protein p53. Both chemicals were metabolized by the abiotic CYP enzyme and the microsomes. CPA showed no activation of p53 and low cytotoxicity without metabolic activation, but strong activation of p53 and increased cytotoxicity upon incubation with liver microsomes or abiotic CYP enzyme. The effect concentration causing a 1.5-fold induction of p53 activation was very similar with both metabolization systems (within a factor of 1.5), indicating that genotoxic metabolites were formed at comparable concentrations. BaP also showed low cytotoxicity and no p53 activation without metabolic activation. The activation of p53 was detected for BaP upon incubation with active and inactive microsomes at similar concentrations, indicating experimental artifacts caused by the microsomes or NADPH. The activation of BaP with the abiotic CYP enzyme increased the cytotoxicity of BaP by a factor of 8, but no activation of p53 was detected. The results indicate that abiotic CYP enzymes may present an alternative to rat liver S9 fraction or microsomes for the metabolic activation of test chemicals, which are completely free of animal-derived components. However, an amendment of existing test guidelines would require testing of more chemicals and genotoxicity end points.

Dataset Information

In Vitro Metabolism Study of Seongsanamide A in Human Liver Microsomes Using Non-Targeted Metabolomics and Feature-Based Molecular Networking.

Publications

In Vitro Metabolism Study of Seongsanamide A in Human Liver Microsomes Using Non-Targeted Metabolomics and Feature-Based Molecular Networking.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets