Detection of glutathione conjugates derived from 4-ipomeanol metabolism in bile of rats by liquid chromatography-tandem mass spectrometry
| Autor: | Jiang Zheng, Teresa M. Alvarez-Diez |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Male
Magnetic Resonance Spectroscopy Stereochemistry Pharmaceutical Science Antineoplastic Agents In Vitro Techniques Mass spectrometry Mass Spectrometry Rats Sprague-Dawley chemistry.chemical_compound Cytochrome P-450 Enzyme System Liquid chromatography–mass spectrometry Furan Animals Bile Biotransformation Chromatography High Pressure Liquid Pharmacology Chromatography biology Chemistry Terpenes Selected reaction monitoring Cytochrome P450 Metabolism Glutathione Deuterium Rats Isotope Labeling Microsome biology.protein Microsomes Liver |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 32(12) |
| ISSN: | 0090-9556 |
| Popis: | 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,beta-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. |
| Databáze: | OpenAIRE |
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