Identification of metabolites from Type III F2-isoprostane diastereoisomers by mass spectrometry

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Identification of metabolites from Type III F₂-isoprostane diastereoisomers by mass spectrometry

Chiara Chiabrando^a, Claudia Rivalta^a, Renzo Bagnati^a, Anna Valagussa^a, Thierry Durand^b, Alexandre Guy^b, Pia Villa^a, Jean-Claude Rossi^b, and Roberto Fanelli^a
^a Istituto di Ricerche Farmacologiche ‘Mario Negri,’, Department of Environmental Health Sciences, Via Eritrea 62, 20157 Milano, Italy
^b UMR CNRS 5074, Faculty of Pharmacy, UM I, 15 Av. Ch. Flahault, F-34060 Montpellier, France

Correspondence to: Chiara Chiabrando, To whom correspondence should be addressed., chiabrando{at}marionegri.it (E-mail)

F₂-isoprostanes (F₂-iPs) are prostaglandin (PG)-like productsof non-enzymatic free radical-catalyzed peroxidation of arachidonicacid that are now widely used as indices of lipid peroxidationin vivo. Knowledge of the metabolic fate of F₂-iPs in vivo isstill scant, despite its importance for defining their overallformation and biological effects in vivo. Type III F₂-iPs, whichare diastereoisomers of cyclooxygenase-derived PGF₂, may bemetabolized through the pathways of PG metabolism. We thereforestudied the in vitro metabolism of eight synthetic Type IIIF₂-iP diastereoisomers in comparison with PGF₂. We used gaschromatography-mass spectrometry and high performance liquidchromatography-electrospray-tandem mass spectrometry for structuralidentification of metabolites formed after incubation of thevarious compounds with isolated rat hepatocytes. PGF₂ was metabolizedto several known products, resulting from a combination of ß-oxidation,reduction of ${Delta}$ ⁵ and/or ${Delta}$ ¹³ double bonds, and 15-OH oxidation,plus other novel products deriving from conjugation with taurineof PGF₂ and its metabolites. Of the eight F₂-iP diastereoisomers,some were processed similarly to PGF₂, whereas others showedpeculiar metabolic profiles according to specific stereochemicalconfigurations.

These data represent the first evidence of biodegradation ofselected Type III F₂-iP isomers other than 8-epi-PGF₂, throughknown and novel pathways of PGF₂ metabolism. The analyticalcharacterization of these products may serve as a basis foridentifying the most significant products formed in vivo. —Chiabrando, C., C. Rivalta, R. Bagnati, A. Valagussa, T. Durand,A. Guy, P. Villa, J-C. Rossi, and R. Fanelli. Identificationof metabolites from Type III F₂-isoprostane diastereoisomersby mass spectrometry. J. Lipid Res. 2002. 43: 495–509.

Supplementary key words: PGF₂, taurine conjugation, isolated rat hepatocytes, gas chromatography-massspectrometry, high performance liquid chromatography-electrospray-tandemmass spectrometry

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