Mapping insoluble indole metabolites in the gastrointestinal environment of a murine colorectal cancer model using desorption/ionisation on porous silicon imaging

David Rudd, Kirsten Benkendorff, Charndeep Chahal, Taryn Guinan, Ove Johan Ragnar Gustafsson, Babak Esmaeelian, Hanna Krysinska, Lisa Pogson, Nicolas Hans Voelcker, Catherine Anne Abbott

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Indole derivatives are a structurally diverse group of compounds found in food, toxins, medicines, and produced by commensal microbiota. On contact with acidic stomach conditions, indoles undergo condensation to generate metabolites that vary in solubility, activity and toxicity as they move through the gut. Here, using halogenated ions, we map promising chemo-preventative indoles, i) 6-bromoisatin (6Br), ii) the mixed indole natural extract (NE) 6Br is found in, and iii) the highly insoluble metabolites formed in vivo using desorption/ionisation on porous silicon-mass spectrometry imaging (DIOS-MSI). The functionalised porous silicon architecture allowed insoluble metabolites to be detected that would otherwise evade most analytical platforms, providing direct evidence for identifying the therapeutic component, 6Br, from the mixed indole NE. As a therapeutic lead, 0.025 mg/g 6Br acts as a chemo-preventative compound in a 12 week genotoxic mouse model; at this dose 6Br significantly reduces epithelial cell proliferation, tumour precursors (aberrant crypt foci; ACF); and tumour numbers while having minimal effects on liver, blood biochemistry and weight parameters compared to controls. The same could not be said for the NE where 6Br originates, which significantly increased liver damage markers. DIOS-MSI revealed a large range of previously unknown insoluble metabolites that could contribute to reduced efficacy and increased toxicity.

Original languageEnglish
Article number12342
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

Cite this

Rudd, David ; Benkendorff, Kirsten ; Chahal, Charndeep ; Guinan, Taryn ; Gustafsson, Ove Johan Ragnar ; Esmaeelian, Babak ; Krysinska, Hanna ; Pogson, Lisa ; Voelcker, Nicolas Hans ; Abbott, Catherine Anne. / Mapping insoluble indole metabolites in the gastrointestinal environment of a murine colorectal cancer model using desorption/ionisation on porous silicon imaging. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
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abstract = "Indole derivatives are a structurally diverse group of compounds found in food, toxins, medicines, and produced by commensal microbiota. On contact with acidic stomach conditions, indoles undergo condensation to generate metabolites that vary in solubility, activity and toxicity as they move through the gut. Here, using halogenated ions, we map promising chemo-preventative indoles, i) 6-bromoisatin (6Br), ii) the mixed indole natural extract (NE) 6Br is found in, and iii) the highly insoluble metabolites formed in vivo using desorption/ionisation on porous silicon-mass spectrometry imaging (DIOS-MSI). The functionalised porous silicon architecture allowed insoluble metabolites to be detected that would otherwise evade most analytical platforms, providing direct evidence for identifying the therapeutic component, 6Br, from the mixed indole NE. As a therapeutic lead, 0.025 mg/g 6Br acts as a chemo-preventative compound in a 12 week genotoxic mouse model; at this dose 6Br significantly reduces epithelial cell proliferation, tumour precursors (aberrant crypt foci; ACF); and tumour numbers while having minimal effects on liver, blood biochemistry and weight parameters compared to controls. The same could not be said for the NE where 6Br originates, which significantly increased liver damage markers. DIOS-MSI revealed a large range of previously unknown insoluble metabolites that could contribute to reduced efficacy and increased toxicity.",
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Mapping insoluble indole metabolites in the gastrointestinal environment of a murine colorectal cancer model using desorption/ionisation on porous silicon imaging. / Rudd, David; Benkendorff, Kirsten; Chahal, Charndeep; Guinan, Taryn; Gustafsson, Ove Johan Ragnar; Esmaeelian, Babak; Krysinska, Hanna; Pogson, Lisa; Voelcker, Nicolas Hans; Abbott, Catherine Anne.

In: Scientific Reports, Vol. 9, No. 1, 12342, 01.12.2019.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Rudd, David

AU - Benkendorff, Kirsten

AU - Chahal, Charndeep

AU - Guinan, Taryn

AU - Gustafsson, Ove Johan Ragnar

AU - Esmaeelian, Babak

AU - Krysinska, Hanna

AU - Pogson, Lisa

AU - Voelcker, Nicolas Hans

AU - Abbott, Catherine Anne

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