Gambogic acid (GA) is a promising natural anticancer candidate. Although the anticancer activity of GA has been well demonstrated, information regarding the metabolic fate of GA is limited. Previous studies suggested that GA is mainly excreted into intestinal tract in rats through bile after intravenous administration, whereas only traces appeared in the feces, suggesting that GA is metabolized extensively in the intestine. However, there has been no report about the intestinal metabolism of GA either in animals or humans. In this study, large amounts of two sulfonic acid metabolites of GA were found in the feces samples of rats after intravenous administration, and their structures were identified as 10-α sulfonic acid GA and 10-β sulfonic acid GA by comparison of the retention times and spectral data with those of synthesized reference substances using liquid chromatography-diode array detector-tandem mass spectrometry. This rare intestinal metabolic pathway mainly involves Michael addition of the sulfite ion to the 9,10 carbon–carbon double bond of α,β-unsaturated ketone. In addition, a more detailed metabolic profile in rats is proposed, according to the results of in vitro and in vivo studies. It was found that GA can be metabolized by a variety of routes, including monooxidation, hydration, glutathionylation, glucuronidation, and glucosidation in the liver of rats. These findings provide information on the major metabolic soft spot of GA in the intestine and liver of rats, which is not only useful in the future human metabolic study of this compound but also of value in the metabolic studies of GA analogs.
Footnotes
This work was supported by the National Natural Science Foundation of China [Grant 81072609].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.037044.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- GA
- gambogic acid
- UDPGA
- UDP-glucuronic acid
- RLM
- rat liver microsome
- HPLC
- high-performance liquid chromatography
- 10-α SGA
- 10-α sulfonic acid GA
- 10-β SGA
- 10-β sulfonic acid GA
- MS
- mass spectrometry
- 10-GGA
- 10-glutathionyl GA
- P450
- cytochrome P450
- GST
- glutathione transferase
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- DAD
- diode array detector
- ESI
- electrospray ionization
- CID
- collision-induced dissociation
- NOESY
- nuclear Overhauser effect spectroscopy
- SULT
- sulfotransferase
- S-23121
- N-[4-chloro-2-fluoro-5-[(1-methyl-2-propynyl)oxy]phenyl]-3,4,5,6-tetrahydrophthalimide.
- Received November 5, 2010.
- Accepted December 29, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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