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In vitro glucuronidation of methyl gallate and pentagalloyl glucopyranose by liver microsomes.

ABSTRACT: Methyl gallate (MG) and pentagalloyl glucopyranose (PGG) are bioactive phenolic compounds that possess various pharmacological activities. However, the knowledge of hepatic metabolism of MG and PGG is limited. The purpose of this study was to investigate the in vitro glucuronidation of MG and PGG using liver microsomes from human (HLMs) and rats (Sprague-Dawley, SDRLMs; Wistar, WRLMs; and Gunn, GRLMs), and recombinant human uridine 5'-diphospho-glucuronosyltransferases (UGT) 1A1 and 1A9. The results demonstrated that liver microsomes catalyzed two mono-glucuronided MG (M1 and M2) formations but that UGT1A1 and 1A9 catalyzed only M1 formation. For PGG, a mono-glucuronided metabolite was mediated by liver microsomes or UGT1A9. However, a PGG glucuronide was absent in the UGT1A1 system. Additionally, all metabolites showed susceptibility to ?-glucuronidases. Furthermore, the glucuronidation activities of PGG were lower than those of MG. The kinetic parameters of MG glucuronidation demonstrated that the SDRLMs and GRLMs were more similar to the HLMs than the WRLMs for the formations of M1 and M2, respectively and that the SDRLMs and HLMs preferentially contributed to M1, whereas the WRLMs and GRLMs showed the favored formation of M2. In conclusion, MG and PGG were subjectively glucuronided by liver microsomes to demonstrate species- and strain-dependent metabolism.

SUBMITTER: Jiamboonsri P

PROVIDER: S-EPMC7671852 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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In vitro glucuronidation of methyl gallate and pentagalloyl glucopyranose by liver microsomes.

Jiamboonsri Pimsumon P Pithayanukul Pimolpan P Bavovada Rapepol R Leanpolchareanchai Jiraporn J Gao Song S Hu Ming M

Drug metabolism and pharmacokinetics 20160416 4

Methyl gallate (MG) and pentagalloyl glucopyranose (PGG) are bioactive phenolic compounds that possess various pharmacological activities. However, the knowledge of hepatic metabolism of MG and PGG is limited. The purpose of this study was to investigate the in vitro glucuronidation of MG and PGG using liver microsomes from human (HLMs) and rats (Sprague-Dawley, SDRLMs; Wistar, WRLMs; and Gunn, GRLMs), and recombinant human uridine 5'-diphospho-glucuronosyltransferases (UGT) 1A1 and 1A9. The res ...[more]

PMID: 27325020

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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 glucuronidation of methyl gallate and pentagalloyl glucopyranose by liver microsomes.

Publications

In vitro glucuronidation of methyl gallate and pentagalloyl glucopyranose by liver microsomes.

Similar Datasets

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