Analytik von CYP-Eicosanoiden und ihre Rolle bei ischämischem Organversagen
Cytochrome P450 (CYP) enzymes contribute to the bioactivation of long-chain polyunsaturated fatty acids. The monoepoxy- and monohydroxy-metabolites generated by CYP enzymes are collectively termed CYP-eicosanoids. CYP-eicosanoids act as mediators in the regulation of vascular tone, heart- and kidney function and several further physiological processes, mostly in a regio- and stereospecific manner. Arachidonic acid-derived epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid
... etraenoic acid (20-HETE) are prominent members of the CYP-eicosanoid family. EETs and 20-HETE show partially opposing biological activities that contribute to the activation or inhibition of anti-inflammatory and other cell- and organ-protective mechanisms. The aim of the present work was to study the role of CYP-eicosanoids in ischemia/reperfusion (I/R) related organ damage by analyses of endogenous metabolite profiles. The main results were (i) discovery and characterization of the EETs protective role in animal models of the initiation phase of acute kidney injury (AKI) and the therapeutic potential of stable EET-analogs, (ii) identification of 8,9-EET and 20-HETE as potential predictive biomarkers for AKI in patients who underwent open heart surgery, (iii) the development and validation of a novel analytical method for chiral lipidomics (chiral LC-ESI-MS/MS) that allows to study endogenous enantiomers of monohydroxy- and monoepoxy-eicosanoids in complex matrices of biological and clinical samples. Furthermore, the approach was applied to describe the stereospecific regulation of EETs by epoxide hydrolases in vitro and in vivo.