期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 105, 期 2, 页码 808-816出版社
WILEY-BLACKWELL
DOI: 10.1016/j.xphs.2015.10.010
关键词
daphnetin; methylation; glucuronidation; sulfonation; 8-O-methyldaphnetin; anti-inflammatory activity
资金
- National Science & Technology Major Project of China [2012ZX09506001, 2012ZX10002011]
- International Science and Technology Cooperation Program of China [2012DFG32090]
- National Natural Science Foundation of China [81273590, 81302793, 81473181]
Our previous study demonstrated that daphnetin is subject to glucuronidation in vitro. However, daphnetin metabolism is still poorly documented. This study aimed to investigate daphnetin metabolism and its consequent effect on the bioactivity. Metabolic profiles obtained by human liver S9 fractions and human hepatocytes showed that daphnetin was metabolized by glucuronidation, sulfonation, and methylation to form 6 conjugates which were synthesized and identified as 7-O-glucuronide, 8-O-glucuronide, 7-O-sulfate and 8-O-sulfate, 8-O-methylate, and 7-O-suflo-8-O-methylate. Regioselective 8-O-methylation of daphnetin was investigated using in silico docking calculations, and the results suggested that a close proximity (2.03 A) of 8-OH to the critical residue Lysine 144 might be the responsible mechanism. Compared with glucuronidation and sulfonation pathways, the methylation of daphnetin had a high clearance rate (470 mu L/min/mg) in human liver S9 fractions and contributed to a large amount (37.3%) of the methyl-derived metabolites in human hepatocyte. Reaction phenotyping studies showed the major role of SULT1A1, -1A2, and -1A3 in daphnetin sulfonation, and soluble COMT in daphnetin 8-O-methylation. Of the metabolites, only 8-O-methyldaphnetin exhibited an inhibitory activity on lymphocyte proliferation comparable to that of daphnetin. In conclusion, methylation is a crucial pathway for daphnetin clearance and might be involved in pharmacologic actions of daphnetin in humans. (C) 2016 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.
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