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Eudesmin, a bioactive lignan derived from <i>Zanthoxylum armatum</i>
DC., exhibits various pharmacological activities including anticancer,
anti-inflammatory, antifibrotic, neuroprotective, and vasorelaxant effects.
This study compared the metabolic profiles of eudesmin in human and mouse
hepatocytes using liquid chromatography–high-resolution mass spectrometry. We
also identified the human cytochrome P450 (CYP), UDP-glucuronosyltransferase,
and sulfotransferase enzymes responsible
for eudesmin metabolism. The hepatic extraction ratios in human and mouse were 0.59
and 0.61, respectively, indicating moderate hepatic metabolism. Ion identity
molecular networking revealed two metabolite clusters predicted to undergo <i>O</i>-demethylation,
<i>O</i>-didemethylation, hydroxylation, glucuronidation, and sulfation. In
human hepatocytes, eudesmin was metabolized to 5 phase I metabolites, including
<i>O</i>-desmethyleudesmin (M1 and M2), <i>O</i>-didesmethyleudesmin (M3 and
M4), and hydroxyeudesmin (M5), and 8 phase II metabolites including glucuronides
of M1–M4 (M1-G-M4-G), sulfates
of M1–M3 (M1-S-M3-S), and
disulfate of M3. However, 3 phase I metabolites (M1, M2, and M5) and 4 phase II
metabolites (M1-G, M2-G, M1-S, and M2-S) were observed in mouse hepatocytes. M1
was mainly formed by CYP2C8, CYP2C9, CYP2C19, CYP3A4, and CYP3A5; M2–M4 by
CYP2C9 and CYP2C19; and M5 by CYP3A4 and CYP3A5. These findings contribute to prediction
of the pharmacokinetics and metabolism of eudesmin in humans.
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