Abstract
Luteolin partially exerts its biologic effects via its metabolites catalyzed by UDP-glucuronosyltransferases (UGTs) and catechol-O-methyltransferases (COMTs). However, the interplay of UGTs and COMTs in mediating luteolin disposition has not been well clarified. In this study, we investigated the glucuronidation and methylation pathways of luteolin mediated by the interplay of UGTs and COMTs in vivo and in vitro. A total of nine luteolin metabolites was detected in rat plasma and bile by liquid chromatography–tandem mass spectrometry, namely, three glucuronides, two methylated metabolites, and four methylated glucuronides. Luteolin-3′-glucuronide (Lut-3′-G) exhibited the highest systemic exposure among these metabolites. Kinetics studies in rat liver S9 fractions suggested two pathways, as follows: 1) Luteolin was glucuronidated to luteolin-7-glucuronide, luteolin-4′-glucuronide, and Lut-3′-G by UGTs, and then Lut-7-G was methylated to chrysoeriol-7-glucuronide and diosmetin-7-glucuronide by COMTs. 2) Alternatively, luteolin was methylated to chrysoeriol and diosmetin by COMTs, and then chrysoeriol and diosmetin were glucuronidated by UGTs to their respective glucuronides. The methylation rate of luteolin was significantly increased by the absence of glucuronidation, whereas the glucuronidation rate was increased by the absence of methylation, but to a lesser extent. In conclusion, two pathways mediated by the interplay of UGTs and COMTs are probably involved in the metabolic disposition of luteolin. The glucuronidation and methylation of luteolin compensate for each other, although glucuronidation is the predominant pathway.
Footnotes
- Received September 28, 2016.
- Accepted December 27, 2016.
This work was supported by the joint fund set up by the National Natural Science foundation of China and the Government of the Xinjiang Uygur Autonomous Region [Grant U1203204]; the Key International Joint Research Project of National Natural Science Foundation of China [Grant 81120108025]; the Science and Technology Project of Guangzhou City [Grant 201509010004]; and the Natural Science Foundation of Guangdong Province [Grant 2015A030312012].
There is no financial conflict of interests with the authors of this paper. Publication of this paper will not benefit or adversely affect the financial situations of the authors.
↵1 L.W. and Q.C. contributed equally to this paper.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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