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Metabolism of flavonolignans in human hepatocytes

J. Vrba, B. Papoušková, L. Roubalová, M. Zatloukalová, D. Biedermann, V. Křen, K. Valentová, J. Ulrichová, J. Vacek,

. 2018 ; 152 (-) : 94-101. [pub] 20180131

Language English Country England, Great Britain

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc18033335

This study examined the in vitro biotransformation of eight structurally related flavonolignans, namely silybin, 2,3-dehydrosilybin, silychristin, 2,3-dehydrosilychristin, silydianin, 2,3-dehydrosilydianin, isosilybin A and isosilybin B. The metabolic transformations were performed using primary cultures of human hepatocytes and recombinant human cytochromes P450 (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4). The metabolites produced were analyzed by ultra-performance liquid chromatography coupled with tandem mass spectrometry. We found that each of the tested compounds was metabolized in vitro by one or more CYP enzymes, which catalyzed O-demethylation, hydroxylation, hydrogenation and dehydrogenation reactions. In human hepatocytes, silybin, 2,3-dehydrosilybin, silychristin, 2,3-dehydrosilychristin, and isosilybins A and B were directly conjugated by sulfation or glucuronidation. Moreover, isosilybin A was also converted to a methyl derivative, while isosilybin B was hydroxylated and methylated. Silydianin and 2,3-dehydrosilydianin were found to undergo hydrogenation and/or glucuronidation. In addition, 2,3-dehydrosilydianin was found to be metabolically the least stable flavonolignan in human hepatocytes, and its main metabolite was a cleavage product corresponding to a loss of CO. We conclude that the hepatic biotransformation of flavonolignans primarily involves the phase II conjugation reactions, however in some cases the phase I reactions may also occur. These results are highly relevant for research focused on flavonolignan metabolism and pharmacology.

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$a Vrba, Jiří $u Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc 77515, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc 77515, Czech Republic.
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$a Metabolism of flavonolignans in human hepatocytes / $c J. Vrba, B. Papoušková, L. Roubalová, M. Zatloukalová, D. Biedermann, V. Křen, K. Valentová, J. Ulrichová, J. Vacek,
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$a This study examined the in vitro biotransformation of eight structurally related flavonolignans, namely silybin, 2,3-dehydrosilybin, silychristin, 2,3-dehydrosilychristin, silydianin, 2,3-dehydrosilydianin, isosilybin A and isosilybin B. The metabolic transformations were performed using primary cultures of human hepatocytes and recombinant human cytochromes P450 (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4). The metabolites produced were analyzed by ultra-performance liquid chromatography coupled with tandem mass spectrometry. We found that each of the tested compounds was metabolized in vitro by one or more CYP enzymes, which catalyzed O-demethylation, hydroxylation, hydrogenation and dehydrogenation reactions. In human hepatocytes, silybin, 2,3-dehydrosilybin, silychristin, 2,3-dehydrosilychristin, and isosilybins A and B were directly conjugated by sulfation or glucuronidation. Moreover, isosilybin A was also converted to a methyl derivative, while isosilybin B was hydroxylated and methylated. Silydianin and 2,3-dehydrosilydianin were found to undergo hydrogenation and/or glucuronidation. In addition, 2,3-dehydrosilydianin was found to be metabolically the least stable flavonolignan in human hepatocytes, and its main metabolite was a cleavage product corresponding to a loss of CO. We conclude that the hepatic biotransformation of flavonolignans primarily involves the phase II conjugation reactions, however in some cases the phase I reactions may also occur. These results are highly relevant for research focused on flavonolignan metabolism and pharmacology.
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$a Papoušková, Barbora $u Regional Centre of Advanced Technologies and Materials, Department of Analytical Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, Olomouc 77146, Czech Republic.
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$a Roubalová, Lenka $u Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc 77515, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc 77515, Czech Republic.
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$a Zatloukalová, Martina $u Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc 77515, Czech Republic.
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$a Biedermann, David $u Institute of Microbiology of the Czech Academy of Sciences, Laboratory of Biotransformation, Vídeňská 1083, Prague 14220, Czech Republic.
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$a Křen, Vladimír $u Institute of Microbiology of the Czech Academy of Sciences, Laboratory of Biotransformation, Vídeňská 1083, Prague 14220, Czech Republic.
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$a Valentová, Kateřina $u Institute of Microbiology of the Czech Academy of Sciences, Laboratory of Biotransformation, Vídeňská 1083, Prague 14220, Czech Republic.
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$a Ulrichová, Jitka $u Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc 77515, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc 77515, Czech Republic.
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$a Vacek, Jan $u Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc 77515, Czech Republic. Electronic address: jan.vacek@upol.cz.
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