Maximal exercise and plasma cytochrome P450 and lipoxygenase mediators: a lipidomics study

Epoxides derived from arachidonic acid (AA) are released during exercise and may contribute to vasodilation. However, exercise may also affect circulating levels of other epoxides derived from cytochromes P450 (CYP) monooxygenase and lipoxygenase (LOX) pathways, many of whose exhibit cardiovascular activity in vitro. The effects of exercise on their levels have not been documented. We tested the hypothesis that acute, maximal exercise would influence the plasma concentrations of these vasoactive substances. We measured plasma CYP and LOX mediators derived from both the n - 3 and n - 6 fatty acid (FA) classes in healthy volunteers before, during and after short-term exhaustive exercise. Lipid mediators were profiled by means of LC-MS/MS tandem mass spectrometry. A maximal Bruce treadmill test was performed to voluntary exhaustion. Exhaustive exercise increased the circulating levels of epoxyoctadecenoic (12,13-EpOME), dihydroxyeicosatrienoic (5,6-DHET), dihydroxyeicosatetraenoic acids (5,6-DiHETE, 17,18-DiHETE), but had no effect on the majority of CYP and LOX metabolites. Although our calculations of diol/epoxide ratios revealed preferred hydrolysis of epoxyeicosatrienoic acids (EEQs) into their diols (DiHETEs), this hydrolysis was resistant to maximal exercise. Our study is the first documentation that bioactive endogenous n - 3 and n - 6 CYP lipid mediators are released by short-term exhaustive exercise in humans. In particular, the CYP epoxy-metabolite status, 12,13-EpOME/DiHOME, 5,6-EET/DHET, 5,6-EEQ/DiHETE and 17,18-EEQ/DiHETE may contribute to the cardiovascular response during maximal exercise.