Prostanoid Metabolites as Biomarkers in Human Disease

Abstract

Prostaglandins (PGD₂, PGE₂, PGF_2α), prostacyclin (PGI₂), and thromboxane A₂ (TXA₂) together form the prostanoid family of lipid mediators. As autacoids, these five primary prostanoids propagate intercellular signals and are involved in many physiological processes. Furthermore, alterations in their biosynthesis accompany a wide range of pathological conditions, which leads to substantially increased local levels during disease. Primary prostanoids are chemically instable and rapidly metabolized. Their metabolites are more stable, integrate the local production on a systemic level, and their analysis in various biological matrices yields valuable information under different pathological settings. Therefore, prostanoid metabolites may be used as diagnostic, predictive, or prognostic biomarkers in human disease. Although their potential as biomarkers is great and extensive research has identified major prostanoid metabolites that serve as target analytes in different biofluids, the number of studies that correlate prostanoid metabolite levels to disease outcome is still limited. We review the metabolism of primary prostanoids in humans, summarize the levels of prostanoid metabolites in healthy subjects, and highlight existing biomarker studies. Since analysis of prostanoid metabolites is challenging because of ongoing metabolism and limited half-lives, an emphasis of this review lies on the reliable measurement and interpretation of obtained levels.

Keywords: LC–MS/MS; biomarker; creatinine; eicosanoid; metabolism; prostacyclin; prostaglandin; prostanoid; thromboxane.

Figure 1

Schematic overview of the prostanoid pathway with the major metabolites that can be detected in human plasma or urine, respectively. The individual metabolites are described in detail in the text. Metabolites on a red background are regarded as major plasma metabolites; metabolites on a yellow background are major urinary metabolites. Red arrows indicate reduction, green, blue, or yellow arrows oxidation, and grey arrows non-enzymatic reactions. 1, Cyclooxygenase-1/2 (COX, EC 1.14.99.1); 2, Prostacyclin Synthase (PTGIS, EC 5.3.99.4); 3, Thromboxane A Synthase (TBXAS1, EC 5.3.99.5); 4, Hematopoietic Prostaglandin D Synthase (HPGDS, EC 2.5.1.18); 5, Lipocalin-Type Prostaglandin D Synthase (L-PGDS, EC 5.3.99.2); 6, Microsomal Prostaglandin E Synthase-1 (MPGES1, EC 5.3.99.3); 7, Microsomal Prostaglandin E Synthase-2 (MPGES2, EC 5.3.99.3); 8, Cytosolic Prostaglandin E Synthase (CPGES, EC 5.3.99.3); 9, Prostaglandin F Synthase (PGFS; EC 1.1.1.188); 10, non-enzymatic degradation; 11, albumin-mediated degradation; 12, 11-hydroxy Thromboxane Dehydrogenase (EC 1.2.1.3); 13, 15-hydroxyprostaglandin Dehydrogenase (15-PGDH, EC 1.1.1.141); 14, 15-oxo-prostaglandin Δ13-reductase (EC 1.3.1.48); 15, NADPH-dependent PGD₂ 11-ketoreductase (EC 1.1.1.188); 16, enzymatic β-oxidation; 17, enzymatic ω-oxidation.

Figure 2

Major metabolic pathway of PGE₂. Metabolites on a red background are regarded as major plasma metabolites; metabolites on a yellow background are major urinary metabolites. The red arrow indicates reduction, the green, blue, or yellow arrows oxidation, and the grey arrows non-enzymatic/albumin mediated reactions. 1, 15-hydroxyprostaglandin Dehydrogenase (15-PGDH, EC 1.1.1.141); 2, 15-oxo-prostaglandin Δ13-reductase (EC 1.3.1.48); 3, enzymatic β-oxidation; 4, enzymatic ω-oxidation; 5, non-enzymatic degradation; 6, albumin-mediated degradation.

Figure 3

Major metabolic pathways of PGD₂. Metabolites on a red background are regarded as major plasma metabolites; metabolites on a yellow background are major urinary metabolites; metabolites on a grey background are cyclopentenone derivatives of PGD₂. Red arrows indicate reduction, green, blue, or yellow arrows oxidation, and grey arrows non-enzymatic/albumin mediated reactions. The letters in the lower left corner denote the ring structure of the respective metabolite. 1, 15-hydroxyprostaglandin Dehydrogenase (15-PGDH, EC 1.1.1.141); 2, 15-oxo-prostaglandin Δ13-reductase (EC 1.3.1.48); 3, enzymatic β-oxidation; 4, enzymatic ω-oxidation; 5, NADPH-dependent PGD₂ 11-ketoreductase (EC 1.1.1.188); 6, albumin-mediated degradation; 7, non-enzymatic degradation.

Figure 4

Major metabolic pathway of PGF_2α. Metabolites on a red background are regarded as major plasma metabolites; metabolites on a yellow background are major urinary metabolites. The red arrow indicates reduction, and the green, blue, or yellow arrows oxidation reactions. 1, 15-hydroxyprostaglandin Dehydrogenase (15-PGDH, EC 1.1.1.141); 2, 15-oxo-prostaglandin Δ13-reductase (EC 1.3.1.48); 3, enzymatic β-oxidation; 4, enzymatic ω-oxidation.

Figure 5

Major metabolic pathway of TXA₂. Metabolites on a red background are regarded as major plasma metabolites; metabolites on a yellow background are major urinary metabolites. The grey arrow indicates non-enzymatic decomposition, the green and blue arrows oxidation reactions. 1, non-enzymatic degradation; 2, 11-hydroxy Thromboxane Dehydrogenase (EC 1.2.1.3); 3, enzymatic β-oxidation.

Figure 6

Major metabolic pathway of PGI₂. Metabolites on a red background are regarded as major plasma metabolites; metabolites on a yellow background are major urinary metabolites The grey arrow indicates non-enzymatic decomposition and the blue arrow oxidation reactions. 1, non-enzymatic degradation; 2, enzymatic β-oxidation.