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Drug Metabolism and Disposition Fast Forward
First published on August 24, 2004; DOI: 10.1124/dmd.104.000406

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Received for publication May 3, 2004.
Revised August 20, 2004.
Accepted for publication August 23, 2004.

Detection of Glutathione Conjugates Derived from 4-Ipomeanol Metabolism in Bile of Rats by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)

Teresa M. Alvarez-Diez 1 Jiang Zheng 1*

1 Northeastern University

* Address correspondence to: E-mail: j.zheng{at}neu.edu

Abstract

Earlier studies postulated that bioactivation of 4-ipomeanol by P450 enzymes may occur through oxidation of its furan ring, following a similar mechanism to the bioactivation of other furan-containing compounds. This would lead to the formation of furan epoxides and {alpha},{beta}-unsaturated di-aldehyde reactive metabolites that can conjugate with glutathione. These metabolites are though to be responsible for the cytotoxic and anti-cancer properties of 4-ipomeanol. We hypothesized that if 4-ipomeanol is metabolized following this pathway, its glutathione conjugates would be isobaric (molecular ion mass = 492 Da) and would be excreted in bile. To investigate this hypothesis, we analyzed by LC-MS/MS bile of rats administered with a mixture of d0/d6 4-ipomeanol (1:1 ratio) intravenously. Hexadeuterated 4-ipomeanol had all deuterium atoms incorporated on its aliphatic chain. Multiple reaction monitoring scans of bile for the mass transition: MH+/(MH-129)+, which is characteristic of glutathione conjugates, detected 4 glutathione conjugates. The observation of the isotope cluster (M+1)+ (d0) / (MH+6)+ (d6) in a 1:1 molar ratio confirmed that these conjugates derived from 4-ipomeanol. Retention of the 6 deuterium atoms in the glutathione conjugates detected (MH+6)+ indicates that the bioactivation of 4-ipomeanol took place on the furan ring moiety. Rat hepatic microsomal incubations provided additional evidence. From this study, the mass of the reactive metabolites of 4-ipomeanol can be inferred. The inferred mass (186 Da) matches with the mass postulated. A pathway of 4-ipomeanol bioactivation is proposed here. This work represents one step forward into understanding the mechanism of bioactivation of 4-ipomeanol.


Key words: glutathione conjugates, mass spectrometry, reactive metabolites


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L. A. Peterson, M. E. Cummings, C. C. Vu, and B. A. Matter
GLUTATHIONE TRAPPING TO MEASURE MICROSOMAL OXIDATION OF FURAN TO CIS-2-BUTENE-1,4-DIAL
Drug Metab. Dispos., October 1, 2005; 33(10): 1453 - 1458.
[Abstract] [Full Text] [PDF]


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