Semi-Targeted Profiling of Bile Acids by High-Resolution Mass Spectrometry in a Rat Model of Drug-Induced Liver Injury
Using a semi-targeted approach, we have investigated the effect of acetaminophen on circulating bile acid profiles in rats, including many known bile acids and potential isomeric structures, as well as glucuronide and sulfate conjugates. The chromatographic separation was based on an optimized rever...
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/3/2489 |
| _version_ | 1797624272054648832 |
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| author | Myriam Mireault Vivaldy Prinville Leanne Ohlund Lekha Sleno |
| author_facet | Myriam Mireault Vivaldy Prinville Leanne Ohlund Lekha Sleno |
| author_sort | Myriam Mireault |
| collection | DOAJ |
| description | Using a semi-targeted approach, we have investigated the effect of acetaminophen on circulating bile acid profiles in rats, including many known bile acids and potential isomeric structures, as well as glucuronide and sulfate conjugates. The chromatographic separation was based on an optimized reverse-phase method exhibiting excellent resolution for a complex mix of bile acids using a solid-core C18 column, coupled to a high-resolution quadrupole time-of-flight system. The semi-targeted workflow consisted of first assigning all peaks detectable in samples from 46 known bile acids contained in a standard mix, as well as additional peaks for other bile acid isomers. The presence of glucuronide and sulfate conjugates was also examined based on their elemental formulae and detectable peaks with matching exact masses were added to the list of features for statistical analysis. In this study, rats were administered acetaminophen at four different doses, from 75 to 600 mg/kg, with the highest dose being a good model of drug-induced liver injury. Statistically significant changes were found by comparing bile acid profiles between dosing levels. Some tentatively assigned conjugates were further elucidated using in vitro metabolism incubations with rat liver fractions and standard bile acids. Overall, 13 identified bile acids, 23 tentatively assigned bile acid isomers, and 9 sulfate conjugates were found to increase significantly at the highest acetaminophen dose, and thus could be linked to drug-induced liver injury. |
| first_indexed | 2024-03-11T09:40:30Z |
| format | Article |
| id | doaj.art-0c93ee81b0254d7a8fcfebd993f2f215 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:40:30Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0c93ee81b0254d7a8fcfebd993f2f2152023-11-16T16:58:02ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01243248910.3390/ijms24032489Semi-Targeted Profiling of Bile Acids by High-Resolution Mass Spectrometry in a Rat Model of Drug-Induced Liver InjuryMyriam Mireault0Vivaldy Prinville1Leanne Ohlund2Lekha Sleno3Department of Chemistry, Université du Québec à Montréal (UQAM), P.O. Box 8888, Downtown Station, Montreal, QC H3P 3C8, CanadaDepartment of Chemistry, Université du Québec à Montréal (UQAM), P.O. Box 8888, Downtown Station, Montreal, QC H3P 3C8, CanadaDepartment of Chemistry, Université du Québec à Montréal (UQAM), P.O. Box 8888, Downtown Station, Montreal, QC H3P 3C8, CanadaDepartment of Chemistry, Université du Québec à Montréal (UQAM), P.O. Box 8888, Downtown Station, Montreal, QC H3P 3C8, CanadaUsing a semi-targeted approach, we have investigated the effect of acetaminophen on circulating bile acid profiles in rats, including many known bile acids and potential isomeric structures, as well as glucuronide and sulfate conjugates. The chromatographic separation was based on an optimized reverse-phase method exhibiting excellent resolution for a complex mix of bile acids using a solid-core C18 column, coupled to a high-resolution quadrupole time-of-flight system. The semi-targeted workflow consisted of first assigning all peaks detectable in samples from 46 known bile acids contained in a standard mix, as well as additional peaks for other bile acid isomers. The presence of glucuronide and sulfate conjugates was also examined based on their elemental formulae and detectable peaks with matching exact masses were added to the list of features for statistical analysis. In this study, rats were administered acetaminophen at four different doses, from 75 to 600 mg/kg, with the highest dose being a good model of drug-induced liver injury. Statistically significant changes were found by comparing bile acid profiles between dosing levels. Some tentatively assigned conjugates were further elucidated using in vitro metabolism incubations with rat liver fractions and standard bile acids. Overall, 13 identified bile acids, 23 tentatively assigned bile acid isomers, and 9 sulfate conjugates were found to increase significantly at the highest acetaminophen dose, and thus could be linked to drug-induced liver injury.https://www.mdpi.com/1422-0067/24/3/2489acetaminophenbile acidshepatotoxicityliquid chromatography–high resolution mass spectrometrymetabolomicsrat plasma |
| spellingShingle | Myriam Mireault Vivaldy Prinville Leanne Ohlund Lekha Sleno Semi-Targeted Profiling of Bile Acids by High-Resolution Mass Spectrometry in a Rat Model of Drug-Induced Liver Injury International Journal of Molecular Sciences acetaminophen bile acids hepatotoxicity liquid chromatography–high resolution mass spectrometry metabolomics rat plasma |
| title | Semi-Targeted Profiling of Bile Acids by High-Resolution Mass Spectrometry in a Rat Model of Drug-Induced Liver Injury |
| title_full | Semi-Targeted Profiling of Bile Acids by High-Resolution Mass Spectrometry in a Rat Model of Drug-Induced Liver Injury |
| title_fullStr | Semi-Targeted Profiling of Bile Acids by High-Resolution Mass Spectrometry in a Rat Model of Drug-Induced Liver Injury |
| title_full_unstemmed | Semi-Targeted Profiling of Bile Acids by High-Resolution Mass Spectrometry in a Rat Model of Drug-Induced Liver Injury |
| title_short | Semi-Targeted Profiling of Bile Acids by High-Resolution Mass Spectrometry in a Rat Model of Drug-Induced Liver Injury |
| title_sort | semi targeted profiling of bile acids by high resolution mass spectrometry in a rat model of drug induced liver injury |
| topic | acetaminophen bile acids hepatotoxicity liquid chromatography–high resolution mass spectrometry metabolomics rat plasma |
| url | https://www.mdpi.com/1422-0067/24/3/2489 |
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