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

0090-9556/04/3212-1345-1350$20.00
DMD 32:1345-1350, 2004

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DETECTION OF GLUTATHIONE CONJUGATES DERIVED FROM 4-IPOMEANOL METABOLISM IN BILE OF RATS BY LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY

Teresa M. Alvarez-Diez, and Jiang Zheng

Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts

Earlier studies postulated that bioactivation of 4-ipomeanol by cytochrome P450 enzymes may occur through oxidation of its furan ring, following a mechanism similar to the bioactivation of other furan-containing compounds. This would lead to the formation of furan epoxides and {alpha},ß-unsaturated di-aldehyde-reactive metabolites that can conjugate with glutathione. These metabolites are thought to be responsible for the cytotoxic and anticancer 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 liquid chromatography-tandem mass spectrometry the bile of rats administered 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 four glutathione conjugates. The observation of the isotope cluster (M + 1)+ (d0)/(MH + 6)+ (d6) in a 1:1 molar ratio confirmed that these conjugates were derived from 4-ipomeanol. Retention of the six 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 the mass postulated. A pathway of 4-ipomeanol bioactivation is proposed here. This work represents one step forward to understanding the mechanism of bioactivation of 4-ipomeanol.

Address correspondence to: Jiang Zheng, Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, 360 Huntington Avenue, Boston, MA 02115. E-mail: J.zheng{at}neu.edu




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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.
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