Comparative metabolism of fargesin in human, dog, monkey, mouse, and rat hepatocytes

Min Seo Lee; Eun Jeong Park; Yong-Yeon Cho; Joo Young Lee; Han Chang Kang; Hye Suk Lee

doi:10.1007/s43188-023-00211-2

Comparative metabolism of fargesin in human, dog, monkey, mouse, and rat hepatocytes

Toxicol Res. 2023 Sep 26;40(1):125-137. doi: 10.1007/s43188-023-00211-2. eCollection 2024 Jan.

Authors

Min Seo Lee^#¹, Eun Jeong Park^#¹, Yong-Yeon Cho¹, Joo Young Lee¹, Han Chang Kang¹, Hye Suk Lee¹

Affiliation

¹ College of Pharmacy and BK21 Four-sponsored Advanced Program for SmartPharma Leaders, The Catholic University of Korea, Bucheon, 14662 Republic of Korea.

^# Contributed equally.

Abstract

Fargesin, a bioactive lignan derived from Flos Magnoliae, possesses anti-inflammatory, anti-oxidative, anti-melanogenic, and anti-apoptotic effects. This study compared the metabolic profiles of fargesin in human, dog, monkey, mouse, and rat hepatocytes using liquid chromatography-high resolution mass spectrometry. In addition, we investigated the human cytochrome P450 (CYP), UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) enzymes responsible for fargesin metabolism. The hepatic extraction ratio of fargesin among the five species ranged from 0.59 to 0.78, suggesting that it undergoes a moderate-to-extensive degree of hepatic metabolism. During metabolism, fargesin generates three phase 1 metabolites, including fargesin catechol (M1) and O-desmethylfargesin (M2 and M3), and 11 phase 2 metabolites, including O-methyl-M1 (M4 and M5) via catechol O-methyltransferase (COMT), glucuronides of M1, M2, M4, and M5, and sulfates of M1-M5. The production of M1 from fargesin via O-demethylenation is catalyzed by CYP2C9, CYP3A4, CYP2C19, and CYP2C8 enzymes, whereas the formation of M2 and M3 (O-desmethylfargesin) is catalyzed by CYP2C9, CYP2B6, CYP2C19, CYP3A4, CYP1A2, and CYP2D6 enzymes. M4 is metabolized to M4 glucuronide by UGT1A3, UGT1A8, UGT1A10, UGT2B15, and UGT2B17 enzymes, whereas M4 sulfate is generated by multiple SULT enzymes. Fargesin is extensively metabolized in human hepatocytes by CYP, COMT, UGT, and SULT enzymes. These findings help to elucidate the pharmacokinetics and drug interactions of fargesin.

Keywords: Cytochrome P450; Fargesin; Hepatocytes; In vitro metabolism; UDP-glucuronosyltransferase.

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