Yang Li1, Chunxia Xu1, Jinjin Xu1, Zifei Qin2,3, Shishi Li1, Liufang Hu1, Zhihong Yao1,2, Frank J Gonzalez4, Xinsheng Yao1,2. 1. College of Pharmacy, Jinan University, Guangzhou, China. 2. Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China. 3. Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 4. Laboratory of Metabolism, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Abstract
OBJECTIVES: Bavachin is a bioactive natural flavonoid with oestrogen-like activity. Here, we aimed to investigate its metabolic and disposal fates involving in CYPs, UGTs and efflux transporters. METHODS: Phase I metabolism and glucuronidation were performed by human liver microsomes (HLM). Reaction phenotyping and activity correlation analysis were performed to identify the main CYP and UGT isozymes. Chemical inhibition and gene knock-down approaches were employed to explore the function of BCRP and MRPs. KEY FINDINGS: Five phase I metabolites (M1-M5) and three glucuronides (G1-G3) were identified. The CLint values for M4 and G1 by HLM were 127.99 and 1159.07 μl/min per mg, respectively. Reaction phenotyping results suggested CYP1A1 (208.85 μl/min per mg) and CYP2C9 (107.51 μl/min per mg), and UGT1A1 (697.19 μl/min per mg), UGT1A7 (535.78 μl/min per mg), UGT1A8 (247.72 μl/min per mg) and UGT1A9 (783.68 μl/min per mg) all participated in the metabolism of bavachin. In addition, activity correlation analysis also supported the results above. Furthermore, the metabolism exhibited marked species differences, and rabbits were the appropriate model animals. Moreover, MRP4 was identified as the main contributor based on chemical inhibition and gene silencing approaches. CONCLUSIONS: CYP1A1 and CYP2C9, UGT1A1, UGT1A7, UGT1A8 and UGT1A9, and MRP4 all played important roles in the metabolism and disposition of bavachin.
OBJECTIVES: Bavachin is a bioactive natural flavonoid with oestrogen-like activity. Here, we aimed to investigate its metabolic and disposal fates involving in CYPs, UGTs and efflux transporters. METHODS: Phase I metabolism and glucuronidation were performed by human liver microsomes (HLM). Reaction phenotyping and activity correlation analysis were performed to identify the main CYP and UGT isozymes. Chemical inhibition and gene knock-down approaches were employed to explore the function of BCRP and MRPs. KEY FINDINGS: Five phase I metabolites (M1-M5) and three glucuronides (G1-G3) were identified. The CLint values for M4 and G1 by HLM were 127.99 and 1159.07 μl/min per mg, respectively. Reaction phenotyping results suggested CYP1A1 (208.85 μl/min per mg) and CYP2C9 (107.51 μl/min per mg), and UGT1A1 (697.19 μl/min per mg), UGT1A7 (535.78 μl/min per mg), UGT1A8 (247.72 μl/min per mg) and UGT1A9 (783.68 μl/min per mg) all participated in the metabolism of bavachin. In addition, activity correlation analysis also supported the results above. Furthermore, the metabolism exhibited marked species differences, and rabbits were the appropriate model animals. Moreover, MRP4 was identified as the main contributor based on chemical inhibition and gene silencing approaches. CONCLUSIONS: CYP1A1 and CYP2C9, UGT1A1, UGT1A7, UGT1A8 and UGT1A9, and MRP4 all played important roles in the metabolism and disposition of bavachin.
Authors: Thorir D Bjornsson; John T Callaghan; Heidi J Einolf; Volker Fischer; Lawrence Gan; Scott Grimm; John Kao; S Peter King; Gerald Miwa; Lan Ni; Gondi Kumar; James McLeod; R Scott Obach; Stanley Roberts; Amy Roe; Anita Shah; Fred Snikeris; John T Sullivan; Donald Tweedie; Jose M Vega; John Walsh; Steven A Wrighton Journal: Drug Metab Dispos Date: 2003-07 Impact factor: 3.922
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