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Anal Bioanal Chem. 2016 Apr;408(10):2485-95. doi: 10.1007/s00216-016-9345-y. Epub 2016 Feb 11.

Metabolites profiling of 10 bufadienolides in human liver microsomes and their cytotoxicity variation in HepG2 cell.

Author information

1
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
2
Anhui Jinchan Biochemistry Company Ltd., Huaibei, 235000, China.
3
State Intellectual Property Office of the P.R.C, Beijing, 100088, China.
4
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China. hyzhao@icmm.ac.cn.
5
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China. blbian@icmm.ac.cn.

Abstract

Bufadienolides, a class of polyhydroxy steroids, exhibit significant antitumor activity. In this study, a total of 39 metabolites from 10 bufadienolides were detected and identified by ultrahigh-performance liquid chromatography (UHPLC) coupled with an LTQ Orbitrap mass spectrometer. The results showed that hydroxylation and dehydrogenation were the major metabolic pathways of bufadienolides in human liver microsomes (HLMs). CYP3A4 was found to be the major metabolic enzyme and CYP2D6 only mediated the dehydrogenation reaction. A systematic validated cytotoxicity evaluation method for bufadienolide metabolites at equal equivalents was established. Hellebrigenin (1), hellebrigenol (2), arenobufagin (3), bufotalin (5), and bufalin (6) were selected to determine their cytotoxicity against HepG2 cells before and after incubation in HLMs. All the test samples were enriched by a validated solid-phase extraction (SPE) method. Although the cytotoxicities of metabolites were weaker than those of the parent compounds to different degrees, their effects were still strong.

KEYWORDS:

Bufadienolides; CYP2D6; CYP3A4; HepG2 cell line; Metabolites

PMID:
26869342
DOI:
10.1007/s00216-016-9345-y
[Indexed for MEDLINE]

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